Diabetes mellitus

Diabetes mellitus

Clinics in Dermatology (2006) 24, 237 – 246 Diabetes mellitus Intekhab Ahmed, MD*, Barry Goldstein, MD Division of Endocrinology, Diabetes and Metabo...

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Clinics in Dermatology (2006) 24, 237 – 246

Diabetes mellitus Intekhab Ahmed, MD*, Barry Goldstein, MD Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA

Abstract Dermatologic problems are common in diabetes, with approximately 30% of patients experiencing some cutaneous involvement during the course of their illness. Skin manifestations generally appear during the course of the disease in patients known to have diabetes, but they may also be the first presenting sign of diabetes or even precede the diagnosis by many years. The skin involvement can be autoimmune in nature, such as acanthosis nigricans, necrobiosis lipoidica, diabetic dermopathy, scleredema, and granuloma annulare or infectious in the form of erythrasma, necrotizing fasciitis, and mucormycosis. Pharmacologic management of diabetes, in addition, can also result in skin changes, such as lipoatrophy and lipohypertrophy, at the site of injection of insulin, and oral antidiabetic agents can cause multiple skin reactions as adverse effects. The management of these cutaneous manifestations is tailored according to the underlying pathophysiology, but a tight control of blood glucose is a prerequisite in all management strategies. D 2006 Elsevier Inc. All rights reserved.

Introduction Diabetes mellitus is a highly prevalent disease. An estimated 18.2 million people had diabetes in the United States in 2002.1 Worldwide, diabetes is estimated to affect 151 million people, with an increase projected to rise to 324 million by the year 2025.2 More than 80% of cases of diabetes are due to type 2 diabetes mellitus, which typically affects older, overweight, and sedentary individuals and those who have a complex pathophysiology involving resistance to the action of insulin in the body and inadequate insulin secretion from the pancreas. Type 1 diabetes mellitus, characterized by a specific autoimmune destruction of the insulin-secreting b-cells in the pancreatic islets, comprises 5% to 10% of all diabetes. Much less frequently, other specific causes can also lead to diabetes. Dermatologic problems are common in diabetes, with approximately 30% * Corresponding author. Tel.: +1 215 503 1272; fax: +1 215 923 7932. E-mail address: [email protected] (I. Ahmed). 0738-081X/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2006.04.009

of patients experiencing some cutaneous involvement during the course of their illness.3 Consistent with their underlying pathophysiology, autoimmune skin lesions are more common in type 1 diabetics. In type 2 diabetes mellitus, infectious involvement of the skin is more prevalent.4,5 Skin manifestations generally appear during the course of the disease in patients known to have diabetes, but they may also be the first presenting sign of diabetes or even precede the diagnosis by many years. The skin manifestations in diabetics can be grouped as (I) noninfectious, (II) infectious, and related to (III) complications of diabetes treatment.

Clinical presentation of diabetes mellitus Diabetes mellitus is a heterogeneous group of disorders characterized by high serum glucose levels and disturbances of carbohydrate and lipid metabolism. Clinically, diabetes mellitus can be classified as type 1 and type 2. Type 1

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diabetes mellitus is characterized by an abrupt clinical onset, insulin insufficiency, tendency to ketoacidosis even in the basal state, and an absolute dependence on insulin to sustain life. Type 2 diabetes mellitus is a result of dual defect: impaired insulin action (resistance) and impaired b-cell function. Patients with type 2 diabetes mellitus may remain relatively asymptomatic for many years and may show low, normal, or elevated levels of insulin because of insulin resistance. Typical patient with type 2 diabetes mellitus is an obese person with strong family history of diabetes. Obesity in type 2 diabetics tends to be bandroidQ in distribution, that is, more upper body fat deposition (abdomen, chest, neck, and face) and relatively less fat deposits on the extremities. This form of fat deposition is characterized by a high waist to hip ratio. Hypertension and hyperlipidemia frequently accompany such kind of obesity. Patients with both type of diabetes can present with polyuria and thirst, nocturia, blurring of vision, generalized fatigue, recurrent pruritus, and vulvovaginitis (females). They may present to the dermatology clinic with skin lesions, such as acanthosis nigricans, or repeated skin infections.

Diagnostic criteria The following 3 criteria are the most recent recommendations of an international committee of diabetes experts based on the review of epidemiologic data and the relationship between blood glucose and its impact on microvascular complications (retinopathy and nephropathy) in diabetics. 1.

2. 3.

therapeutic treatment. It is considered malignant when it is a paraneoplastic sign of an internal malignancy. There is no difference in the appearance or histology of the lesion itself between these 2 groups. Histopathologically, the lesions reveal papillomatosis, hyperkeratosis, and mild acanthosis. The dark color is due to thickness of the keratin-containing superficial epithelium, because there is no change in melanocyte number or melanin content.7 Benign acanthosis nigricans is most commonly seen in situations of insulin resistance, including type 2 diabetes mellitus,7 obesity,8 total lipodystrophy,9 and polycystic ovarian syndrome.10 Acanthosis nigricans can also be seen in acromegaly,11 Cushing’s syndrome,12 and leprechaunism.13 All of these conditions have in common significant resistance to endogenous insulin, which can circulate at very high levels in these patients. The underlying pathogenesis of the acanthosis is most likely related to the high level of circulating insulin cross-reacting and binding to receptors for the structurally related insulin-like growth factor on keratinocytes and dermal fibroblasts, where it stimulates growth.14 Acanthosis nigricans also occurs rarely as a complication of an internal malignancy, particularly of the stomach,15 and secondary to some medications, including nicotinic acid.16 The exact mechanism of acanthosis nigricans appearance in

Symptoms of diabetes (thirst, increased urination, unexplained weight loss) plus a random plasma glucose level of 200 mg/dL (11.1 mmol/L) or higher; Fasting plasma glucose 126 mg/dL (7.0 mmol/L) or higher after an overnight (at least 8 hours) fast; Two-hour plasma glucose 200 mg/dL (11.1 mmol/L) or higher during a standard 75-g oral glucose tolerance test.

Cutaneous manifestations Noninfectious Acanthosis nigricans Acanthosis nigricans presents clinically as hypertrophic, hyperpigmented, velvety plaques in body folds, mostly the axillae and flexural areas of the posterior neck.6 Other locations include the groin, umbilicus, areolae, submammary regions, and hands (tripe hands) (Fig. 1).7 It is mostly asymptomatic, but can be painful, malodorous, or macerated. The condition varies in severity, from mild discoloration of localized area to generalized skin involvement. Acanthosis nigricans is traditionally classified as benign when it occurs in insulin-resistant states, as in type 2 diabetes mellitus, or as a result of side effect of a

Fig. 1 Acanthosis nigricans in the axillary fold of a patient. Hyperpigmentation and fine velvety appearance of skin can be easily appreciated.

Diabetes mellitus

239 Histopathologically, basement membrane thickening is found in areas of dermopathy (Fig. 2).22 Necrobiosis lipoidica Necrobiosis (degeneration of collagen) lipoidica is a disease of unknown origin, although it occurs in only 0.3% of all patients with diabetes. Of the patients with necrobiosis lipoidica, approximately two thirds are insulin-dependent patients with diabetes.23 The skin lesions may appear years before the onset of diabetes, and most patients with diabetes do not develop necrobiosis lipoidica (Fig. 3). The disease may occur at any age, but it most commonly appears in the third and fourth decades. Most of the patients are females, and in most cases, the lesions are bilateral and confined to the anterior surfaces of the lower legs.24 The eruption begins as an oval violaceous patch and expands slowly. The advancing border is red, and the central area turns yellow-brown. The central area atrophies and has a waxy surface; telangiectasias become prominent. Ulceration occurs in up to 35% of cases.25 Pathologically, the lesions show degeneration of collagen, granulomatous inflammation of subcutaneous tissues and of blood vessels, capillary basement membrane thickening, and obliteration of vessel lumina. The yellow in the central area of the lesions is most likely secondary to thinning of the dermis, making subcutaneous fat more visible.26

Fig. 2 Shin spots begin predominantly on the lower extremities as crops of 4 to 5 dull red macules or papules, 5 to 12 mm in diameter. As the lesions evolve, they become shallow, depressed, and hyperpigmented scars. Also appreciable is the absence of hair, indicating presence of microangiopathy.

patients using nicotinic acid is unknown, but possible hypotheses include insulin resistance caused by the drug17 and disturbance of epidermal lipid homeostasis.18 Evaluation of serum insulin and glucose, either fasting or during an oral glucose tolerance test, could help demonstrate the presence of clinical insulin resistance to verify if it is the cause of acanthosis nigricans in patients without diabetes. Otherwise, a search for an internal malignancy or a drug reaction should be undertaken. Diabetic dermopathy (‘‘shin spots’’) This common skin complication of diabetes occurs in up to 40% of patients.19 Its occurrence in nondiabetics also indicates that the underlying etiology involves more than just hyperglycemia. It occurs twice as frequently in men compared with women.20 Diabetic dermopathy is commonly seen in diabetics with other end-organ damage such as retinopathy, neuropathy, and nephropathy, and some investigators have postulated that the presence of microangiopathy creates an underlying milieu that favors its occurrence.21 Lesions begin predominantly on the lower extremities as crops of 4 to 5 dull red macules or papules, 5 to 12 mm in diameter over a period of a week, and then persist or slowly resolve. As the lesions evolve, they become shallow, depressed, and hyperpigmented scars.

Fig. 3 Necrobiosis lipoidica diabeticorum—an oval violaceous patch showing red border and atrophied central area with waxy surface and telangiectasias. Up to 35% of these lesions result in ulceration.

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I. Ahmed, B. Goldstein the skin can also be manifested by the pebbling of the fingers, the Huntley’s papules or finger pebbles, which are multiple grouped minute papules on the extensor surfaces of the fingers, on or near the knuckles or periungual areas.33 Clinical course is progressive in most of the cases and leads to more extensive involvement and more stiffness.34 Extensive scleredema-like skin changes of the torso and back occur in a subgroup of these patients. The skin changes may occur early in the disease. Scleredema-like skin changes are highly correlated to the joint manifestations of diabetic hand syndrome, which consist of limited joint mobility (LJM), flexion contractures, and trigger finger.35 To demonstrate LJM, the patient attempts to approximate the palmar surfaces of the interphalangeal joints with the fingers fanned (prayer sign).

Fig. 4 Scleredema adultorum of Buschke—asymmetric nonpitting induration of the skin that appears predominantly on the posterolateral aspects of the neck, shoulders, and upper back.

Scleredema (scleredema adultorum of Buschke) Scleredema is an asymmetric nonpitting induration of the skin that appears predominantly on the posterolateral aspects of the neck, shoulders, and upper back. It is a fairly common clinical entity that has been reported in the dermatology literature as having a similar pathogenesis as the diabetic hand syndrome.27,28 The reduced elasticity of the skin tissue in diabetes results in reduced joint mobility. Depending on the series, the incidence of scleredema ranges between 10% and 50% of patients.29 It affects patients with types 1 and 2 diabetes mellitus without any racial or sex preference. Skin and joint findings are frequently coexistent in most cases, although they may occur independently (Fig. 4).30 Histologically, the dermis is markedly thickened as a result of the replacement of subcutaneous fat by connective tissue. Collagen and glycosaminoglycans are increased, proportional to the increase in skin thickness.31 In diabetics, fibroblasts secrete a different proportion of heparan sulfate and dermatan sulfate,32 suggesting that diabetes in these patients can influence the composition of connective tissue. Clinically, scleredema presents as bilateral, symmetrical, and painless thickening and induration of the skin on the dorsum of the fingers (sclerodactyly) and proximal interphalangeal joints, and may involve the metacarpophalangeal joint. It can extend beyond, to the forearm, arms, and back. The skin may have a waxy appearance. The thickening of

Granuloma annulare Granuloma annulare is a form of dermatitis with histologic similarities to necrobiosis lipoidica.14 It can involve the skin in a variety of ways. Clinically, there is a localized form seen in young patients, characterized by a ring of small, firm, flesh-colored, or red papules, most frequently found on the lateral or dorsal surfaces of the hands and feet. The disease begins with an asymptomatic flesh-colored papule that undergoes central involution. Over months, a ring of papules slowly increases in diameter to 0.5 to 5 cm. The duration of the disease is highly variable. Many lesions undergo spontaneous involution without scarring, whereas others may last for years.36 A disseminated form of granuloma annulare may occur in adults and appears with numerous flesh-colored or erythematous papules, some of which form annular rings. The papules may be accentuated in sun-exposed areas. A generalized perforating granuloma annulare is characterized by 1- to 4-mm umbilicated papules on the extremities and is most commonly seen in children and young adults. Biopsy shows transepithelial elimination of degenerating collagen fibers. A high incidence of perforating granuloma annulare has been reported in the Hawaiian Islands.35 The association of granuloma annulare with diabetes mellitus is controversial, however. A case-control study failed to reveal any statistically significant correlation between granuloma annulare and type 2 diabetes mellitus,36 whereas in a retrospective study, 12% of patients with granuloma annulare had diabetes mellitus. Those patients suffered significantly more often from chronic relapsing granuloma annulare than nondiabetic patients.37 Yellow skin (carotenodermia) Rarely, the skin of patients with diabetes may appear yellowish, secondary to deposition of carotenoids in the elastic tissue of the skin.11 Carotenoids are pigments present in green and yellow vegetables, and often, their blood levels are elevated in diabetic patients.38 Other endocrine disorders associated with a yellow complexion include hypothyroidism, hypogonadism, hypopituitarism, bulimia, and anorexia nervosa.14

Diabetes mellitus Diabetic bullae These lesions occur most commonly in patients with longstanding diabetes, although they have been reported as the initial presentation of diabetes.39 No sex preference has been noted.40 The lesions are of uncertain cause, characterized by the rapid onset of unilateral or bilateral tense, serous blisters of varying sizes from 0.5 to 3 cm, on the planter surfaces and margins of the feet.41 The lesions can also occur on the hands and legs. These blisters are painless and, in the absence of trauma or denudation of the skin, usually heal in 2 to 4 weeks.42 Histologically, diabetic bullae are subepidermal, with early reepithelialization.43 Acrochordons (skin tags) Approximately 66% to 75% of the patients with skin tags have diabetes. These soft tissue fibromas have predilection for eyelids, neck, and axilla, and incidence increases with age. In a study by Darmstadt et al,44 120 patients with acrochordon were evaluated for the presence of impaired carbohydrate metabolism. Overt diabetes with hyperglycemia was found in 88 patients; and glucose intolerance was detected in 6 patients; 4 patients had reactive hypoglycemia.

Treatment of noninfectious skin disorders Acanthosis nigricans The most effective treatment of benign acanthosis nigricans is lifestyle alteration with weight reduction and exercise to reduce insulin resistance. In virtually all cases, the acanthosis is asymptomatic and does not require any pharmacologic treatment, although when severe, it may present a cosmetic problem. Reducing thicker lesions in areas of maceration may decrease odor and promote comfort. Lac-Hydrin, a 12% lactic acid cream, may soften lesions. Retinoic acid can be applied if irritation occurs.45 Oral isotretinoin (Accutane) is useful, but acanthosis nigricans recurs when the drug is discontinued.25 Clinical improvement with dietary fish oil supplementation has also been reported.18 Necrobiosis lipoidica There is no standard treatment of necrobiosis lipoidica. Current treatment options mainly rely on the use of glucocorticoids in topical, intralesional, or systemic forms.46 Some studies have used pentoxifylline47 with some success, because it may target the underlying microangiopathy. Oral aspirin,48 chloroquine,49 and cyclosporin50 have also been used in resistant cases with some success. Skin grafting may be effective in extensive disease.36 Granuloma annulare Localized lesions are asymptomatic and are best left untreated. Those patients troubled by appearance may be treated with intralesional injections of triamcinolone acetonide (2.5-5 mg/mL). Topical steroids have little effect. Atrophy is a possible side effect.51 A single 10- to 60-second freeze-thaw cycle using nitrous oxide or liquid nitrogen applied with closed probes produced resolution in 80.6%

241 of patients.52 Disseminated granuloma annulare has been treated successfully with dapsone,37 isotretinoin,38 and psoralen–UV-A.53 Scleredema Although generally refractory to treatment, several therapeutic modalities have been attempted with some success. These include extracorporeal photopheresis,54 radiotherapy, electron beam radiation,55 psoralen–UV-A photochemotherapy,56 prostaglandin E1,57 cyclosporin,58 and high-dose penicillin. Anecdotal reports have demonstrated that tight glycemic control with insulin pump resulted in decreased skin thickness.59 A study by Eaton et al60 has shown a significant reduction in frequency of LJM in children with type 1 diabetes mellitus screened in 1998 in comparison with those screened in 1976. They suggested this decrease in frequency as a result of improved blood glucose control during the past 2 decades. Use of aldose reductase inhibitor, sorbinil in the dose of 400 mg/d, has shown promising results in the treatment of scleredema-afflicted joints.61 A 10-year follow-up of patients treated with LJM using sorbinol in comparison with historic controls has demonstrated a sustained correction of LJM and lack of side effects.62 Physical therapy is recommended to prevent limitations in range of motion. No trials, however, have been performed to evaluate the benefit of physical therapy. Others Treatment of diabetic dermopathy does not require any specific intervention, except prevention of secondary infection. Diabetic bullae, if large and uncomfortable, drainage and topical antibiotics may be required to prevent secondary infection.14 Skin tags can be removed with laser or shave biopsy.

Skin infections and diabetes Skin infections occur in 20% to 50% of diabetics, more often in patients with type 2 diabetes mellitus. Poor glycemic control is often associated with skin infections, although it can be difficult to determine whether the hyperglycemia is the cause or consequence of the skin infections.14,63 The increased predisposition to infection appears to be secondary to multiple factors, including poor microcirculation, hypohydrosis, peripheral vascular disease, peripheral neuropathy, and the decreased immune response seen in diabetics.64 Some of these factors may also account for poor wound healing in diabetics, because infections can be regarded as a wound in the skin and therefore result in delayed healing. Patients with poor control of their diabetes have an increased rate of colonization, as well as the infections of the skin with Candida albicans, Staphylococcus, and Streptococcus.65 In women, vaginal yeast overgrowth (moniliasis) may be troublesome during hyperglycemicglycosuric phase.66 In men with poor diabetic control,

242 infection of the foreskin (balanitis) can also be a problem.14 Certain cutaneous infections deserve special consideration.

Necrotizing fasciitis An uncommon but potentially lethal skin and soft tissue infection is more common in diabetics.67 The infections are typically of mixed bacterial origin with the most common organisms including Streptococcus pyogenes, Staphylococcus aureus, anaerobic streptococci, and Bacteroides.68 Eighty percent of cases of necrotizing fasciitis occur as an extension of an often trivial skin lesion such as boil, an insect bite, or an injection site. Decubitus ulcers, skin of the perineum, and the extremities are often the sites of initiation, although any part of the body can be affected. Infections involving the scrotum or perineal skin (Fournier’s gangrene) may carry a mortality rate of 40% despite antibiotic use or surgical intervention.69 A high index of suspicion and thorough physical examination is necessary to make an early diagnosis. Clinical decision making needs to be swift because there may be a remarkably rapid progression from a benign infectious process to one associated with extensive destruction of tissue, systemic toxicity, loss of limb, or death.70,71 Necrotizing fasciitis should be considered in diabetic patients with cellulitis who also have systemic signs of infection such as tachycardia, leukocytosis, marked hyperglycemia, or acidosis. In many patients with diabetes, the signs and symptoms heralding a systemic infectious process may not be initially apparent. The absence of pain in patients with diabetes may also be related to peripheral neuropathy, with anesthesia at the site of infection. Erythema may be present diffusely or locally. In some patients, excruciating pain in the absence of any cutaneous findings is the only clue of underlying infection. Within 24 to 48 hours, erythema may develop or darken to a reddish purple, frequently with associated blisters and bullae; bullae can also develop in normalappearing skin. The bullae are initially filled with clear fluid but rapidly take on a blue or maroon appearance. Once the bullous stage is reached, there is already extensive deep soft tissue destruction such as necrotizing fasciitis or myonecrosis; such patients usually exhibit fever and systemic toxicity. Crepitus is present in about 10% of patients.72 Malignant external otitis This is an invasive infection of the external auditory canal and skull base that typically occurs in immunocompromised patients.73 It typically occurs in elderly diabetics and rarely in children.74 A number of factors may underlie the development of malignant external otitis, including microangiopathy of the ear canal, leading to poor perfusion of the pinna and an increase in the pH of ear canal cerumen in diabetic patients.75,76 Interestingly, no direct relationship has been seen between otitis externa and poor glycemic control.77 Pseudomonas aeruginosa is the causative agent in more than 95% of cases.65 Other organisms leading to this infection in

I. Ahmed, B. Goldstein immunocompromised patients include Aspergillus spp,78,79 S aureus,80 Proteus mirabilis,81 and Candida parapsilosis.82 The infection may begin indolently with ear pain and drainage. If untreated, it may involve periaural area and surrounding structures, potentially leading to osteomyelitis of the base of the skull, meningitis, cerebritis, and thrombosis of the intracranial veins.83 Clinical examination reveals tenderness of the pinna and periauricular area with swollen external auditory canal and purulent discharge. Granulation tissue can be present at the junction of the cartilaginous and bony parts of the canal. The diagnosis depends on a high level of clinical suspicion and laboratory studies showing leukocytosis and a strikingly elevated erythrocyte sedimentation rate. Use of computed tomography/magnetic resonance imaging, bone scan, and thallium scan can reveal the extent of bony involvement. Erythrasma A common superficial bacterial skin infection in diabetics begins as a pruritic red-brown patch in the axilla or groin. Other areas of involvement include inframammary areas, interspaces of the toes, and intergluteal and crural folds.84 Corynebacterium minutissimum is the pathogenic organism found on gram staining. The differential diagnosis of erythrasma includes psoriasis, dermatophytosis, candidiasis, and intertrigo, and methods for differentiating include Wood’s light examination and bacterial and mycological cultures. Rhinocerebral mucormycosis Rhinocerebral mucormycosis is a rare but life-threatening complication of diabetes.85 It may be a presenting manifestation of diabetes in the elderly.86 Most of the diabetics afflicted with this infection have diabetic ketoacidosis at the time of diagnosis, although it can also occur in individuals with well-controlled diabetes.87,88 The infectious agent belongs to a class of fungi known as Zygomycetes, which is ubiquitous in nature, and can be found on decaying vegetation and in the soil. The genera most commonly found in human infections are Rhizopus, Absidia, Cunninghamella, Rhizomucor, Syncephalastrum, Saksenaea, Apophysomyces, and Mucor. The presence of hyperglycemia, the acidic conditions, and the increased serum iron levels are growth stimuli for these fungi, conditions commonly present in poorly controlled diabetics.89 The characteristic presentation involves fever, facial cellulitis, periorbital edema, proptosis, and blindness. Facial numbness is frequent and results from infarction of sensory nerves such as branches of the fifth cranial nerve. A black eschar may be visible in the nasal mucosa or the palate, which results from ischemic necrosis of tissues after vascular invasion of the fungus.90 Spread of the infection from the ethmoid sinus to the frontal lobe results in obtundity. Spread from the sphenoid sinuses to the adjacent cavernous sinus can result in cranial nerve palsies, thrombosis of the sinus itself, and involvement of the carotid artery. The diagnosis should be suspected in any poorly controlled diabetic who presents with sinusitis and purulent

Diabetes mellitus nasal discharge, metabolic acidosis, altered mentation, and/or infarcted tissue in the nose or palate. Endoscopic evaluation of the sinuses is indicated to look for tissue necrosis and to obtain specimens for culture. The specimens should be inspected for characteristic broad nonseptate hyphae with right-angle branching using calcofluor white and methenamine silver stains. Further evaluation includes imaging of the head with either computed tomography or magnetic resonance imaging to assess sinus involvement and to evaluate contiguous structures such as the globe and brain.

Treatment of skin infections in diabetes Necrotizing fasciitis Debridement of necrotic tissue is necessary and can be lifesaving to avert the progression of this potentially fatal infectious process. Antibiotics should be started empirically after obtaining blood and tissue culture. Even with optimal medical and surgical treatment, the overall mortality rate is 20% to 30%.42 External otitis media Treatment involves ear canal irrigation, drainage, debridement if necessary, and appropriate antibiotics. Parenteral or oral quinolones can result in a cure rate of more than 90%.91 Prolonged treatment of 6 to 8 weeks is generally recommended, especially in the presence of osteomyelitis. Patients with resistant P aeruginosa require hospitalization for biopsy, debridement, and parenteral antibiotics (generally a prolonged course of an antipseudomonal b-lactam agent with or without an aminoglycoside). If Aspergillus spp are the causative organisms, prolonged treatment (N12 weeks) with amphotericin B is indicated. Hyperbaric oxygen has been used on occasion with mixed results and may be considered as an adjuvant treatment of refractory cases.92 Erythrasma The treatment of choice is erythromycin, 250 mg 4 times daily for 14 days; other appropriate antibiotics include tetracycline or chloramphenicol.93

243 typically show immunologic mediators including immunoglobulin M (IgM), IgE, and C3.96 For unknown reasons, female patients are more likely to develop lipoatrophy, whereas lipohypertrophy is more common in male patients. Lipohypertrophy. Lipohypertrophy is a localized hypertrophy of subcutaneous fat resulting from repeated injections of insulin into a highly circumscribed area. Insulin absorption may be delayed at such sites, leading to problems with glycemic control.97 The hypertrophy appears to be the result of repeated local stimulation of adipocytes by insulin, and it resolves spontaneously by changing the site of insulin injection (Fig. 5). Complications of continuous subcutaneous insulin infusion. Very infrequently, patients using an insulin pump for subcutaneous insulin delivery can experience local infections at the site of needle insertion, allergy to tape and tubing materials, and rarely hard subcutaneous nodules.98 These complications are minimal, with newer infusion sets, especially when combined with a soft Teflon cannula provided with an antibacterial dressing and/or newer adhesive materials with reduced allergic sensitization. Infections in patients using continuous subcutaneous insulin infusion are infrequent. In the Diabetes Control and Complications Trial, a large prospective study that included many patients with type 1 diabetes mellitus, the incidence of skin infections in patients using insulin pumps ranged from 1 event every 8 to 14 years.99

Reactions to oral antidiabetic agents Dermatologic side effects from oral antidiabetic agents include pruritus, erythema multiform, erythema nodosum, urticaria, morbilliform rash, lichenoid eruptions, and photosensitivity.100 Sulfonylureas are the most common agents associated with these abnormalities because they are structurally related to sulfonamides. So far, no dermatologic side effects have been reported with metformin, acarbose, or repaglinide.

Mucormycosis Parenteral amphotericin B is the treatment of choice, along with surgical debridement because the organism may persist in devitalized tissue.94 Dermatologic complications of the treatment of diabetes Immunologic reactions to insulin Lipoatrophy. Lipoatrophy is characterized by a loss of subcutaneous fat at the insulin injection site, which can be a cosmetic concern.95 With the advent of more purified insulin, this phenomenon has decreased in occurrence. The cause of this complication has been attributed to an immunologic reaction because biopsies of the affected area

Fig. 5 Insulin hypertrophy of the skin, resulting from repeated injections in a circumscribed area of the abdominal wall. The hypertrophy appears to be the result of repeated local stimulation of adipocytes by insulin and it resolves spontaneously by changing the site of insulin injection.

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Conclusion Dermatologic manifestations of diabetes are common and should be addressed aggressively. Tight glucose control in diabetics can prevent and minimize most of the infectious skin diseases seen in these patients, although the relationship between tight glucose control and prevention of noninfectious skin disorders is debatable. Skin disorders resulting from treatment of diabetes can be addressed by changing oral medications and continuously rotating insulin injection sites. The advent of new highly purified insulin preparations has resulted in a marked decrease in the incidence of insulin lipoatrophy and lipohypertrophy.

Acknowledgment We are thankful to Dr William James, MD, Department of Dermatology, University of Pennsylvania, Philadelphia, PA, for his contribution of pictures.

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