EPIDEMIOLOGY

Acanthosis nigricans (AN) is a classic dermatologic manifestation of diabetes mellitus that affects men and women of all ages. AN is more common in type 2 diabetes mellitus (2) and is more prevalent in those with darker-skin color. AN is disproportionately represented in African Americans, Hispanics, and Native Americans (3). AN is observed in a variety of endocrinopathies associated with resistance to insulin such as acromegaly, Cushing syndrome, obesity, polycystic ovarian syndrome, and thyroid dysfunction. Unrelated to insulin resistance, AN can also be associated with malignancies such as gastric adenocarcinomas and other carcinomas (4).

PRESENTATION

AN presents chronically as multiple poorly demarcated plaques with grey to dark-brown hyperpigmentation and a thickened velvety to verrucous texture. Classically, AN has a symmetrical distribution and is located in intertriginous or flexural surfaces such as the back of the neck, axilla, elbows, palmer hands (also known as “tripe palms”), inframammary creases, umbilicus, or groin. Affected areas are asymptomatic; however, extensive involvement may cause discomfort or fetor. Microscopy shows hyperkeratosis and epidermal papillomatosis with acanthosis. The changes in skin pigmentation are primarily a consequence of hyperkeratosis, not changes in melanin. AN can present prior to the clinical diagnosis of diabetes; the presence of AN should prompt evaluation for diabetes mellitus and for other signs of insulin resistance.

PATHOGENESIS

The pathogenesis of AN is not completely understood. The predominant theory is that a hyperinsulin state activates insulin growth factor receptors (IGF), specifically IGF-1, on keratinocytes and fibroblasts, provoking cell proliferation, resulting in the aforementioned cutaneous manifestations of AN (5,6).

TREATMENT

Treatment of AN may improve current lesions and prevent future cutaneous manifestations. AN is best managed with lifestyle changes such as dietary modifications, increased physical activity, and weight reduction. In patients with diabetes, pharmacologic adjuvants, such as metformin, that improve glycemic control and reduce insulin resistance are also beneficial (7). Primary dermatologic therapies are usually ineffective especially in patients with generalized involvement. However, in those with thickened or macerated areas of skin, oral retinoids or topical keratolytics such as ammonium lactate, retinoic acid, or salicylic acid can be used to alleviate symptoms (8-10).

EPIDEMIOLOGY

Dermopathy (DD), also known as pigmented pretibial patches or diabetic shin spots, is the most common dermatologic manifestations of diabetes, presenting in as many as one-half of those with diabetes (11). Although disputed, some consider the presence of DD to be pathognomonic for diabetes. DD has a strong predilection for men and those older than 50 years of age (12). Although DD may antecede the onset of diabetes, it occurs more frequently as a late complication of diabetes and in those with microvascular disease. Nephropathy, neuropathy, and retinopathy are regularly present in patients with DD. An association with cardiovascular disease has also been identified, with one study showing 53% of non-insulin-dependent diabetes mellitus with DD had coexisting coronary artery disease (13).

PRESENTATION

DD initially presents with rounded, dull, red papules that progressively evolve over one-to-two weeks into well-circumscribed, atrophic, brown macules with a fine scale (figure 1). Normally after about eighteen to twenty-four months, lesions dissipate and leave behind an area of concavity and hyperpigmentation. At any time, different lesions can present at different stages of evolution. The lesions are normally distributed bilaterally and localized over bony prominences. The pretibial area is most commonly involved, although other bony prominences such as the forearms, lateral malleoli or thighs may also be involved. Aside from the aforementioned changes, patients are otherwise asymptomatic. DD is a clinical diagnosis that should not require a skin biopsy. Histologically, DD is rather nonspecific; it is characterized by lymphocytic infiltrates surrounding vasculature, engorged blood vessels in the papillary dermis, and dispersed hemosiderin deposits. Moreover, the histology varies based on the stage of the lesion. Immature lesions present with epidermal edema as opposed to epidermal atrophy which is representative of older lesions (14).

Figure 1.

Diabetic Dermopathy

PATHOGENESIS

The origin of DD remains unclear, however, mild trauma to affected areas (15), hemosiderin and melanin deposition (16), microangiopathic changes (17), and destruction of subcutaneous nerves (18) have all been suggested.

TREATMENT

Treatment is typically avoided given the asymptomatic and self-resolving nature of DD as well as the ineffectiveness of available treatments. However, DD often occurs in the context of microvascular complications and neuropathies (12); hence, patients need to be examined and followed more rigorously for these complications. Although it is important to manage diabetes and its complications accordingly, there is no evidence that improved glycemic control alters the development of DD.

EPIDEMIOLOGY

Diabetic Foot Syndrome (DFS) encompasses the neuropathic and vasculopathic complications that develop in the feet of patients with diabetes. Although preventable, DFS is a significant cause of morbidity, mortality, hospitalization, and reduction in quality of life of patients with diabetes. The incidence and prevalence of DFS in patients with diabetes is 1% to 4% and 4% to 10%, respectively (19). Furthermore, DFS is slightly more prevalent in type 1 diabetes compared with type 2 diabetes (20). A more comprehensive review of diabetic foot syndrome can be found in The Diabetic Foot chapter of Endotext.

PRESENTATION

DFS presents initially with callosities and dry skin related to diabetic neuropathy. In later stages, chronic ulcers and a variety of other malformations of the feet develop. Between 15% and 25% of patients with diabetes will develop ulcers (21). Ulcers may be neuropathic, ischemic, or mixed. The most common type of ulcers are neuropathic ulcers, a painless ulceration resulting from peripheral neuropathy. Ulcers associated with peripheral vascular ischemia are painful but less common. Ulcers tend to occur in areas prone to trauma, classically presenting at the site of calluses or over bony prominences. It is common for ulcers to occur on the toes, forefoot, and ankles. Untreated ulcers usually heal within one year, however, fifty percent of patients with diabetes will have recurrence of the ulcer within three years (22). The skin of affected patients, especially in those with type 2 diabetes, is more prone to fungal infection and the toe webs are a common port of entry for fungi which can then infect and complicate ulcers (23). Secondary infection of ulcers is a serious complication that can result in gangrenous necrosis, osteomyelitis, and may even require lower extremity amputation. Another complication, diabetic neuro-osteoarthropathy (also known as Charcot foot), is an irreversible debilitating and deforming condition involving progressive destruction of weight-bearing bones and joints. Diabetic neuro-osteoarthropathy occurs most frequently in the feet and can result in collapse of the midfoot, referred to as “rocker-bottom foot.” Moreover, a reduction of the intrinsic muscle volume and thickening of the plantar aponeurosis can cause a muscular imbalance that produces a clawing deformation of the toes. An additional complication of diabetes and neuropathy involving the feet is erythromelalgia. Erythromelalgia presents with redness, warmth, and a burning pain involving the lower extremities, most often the feet. Symptoms may worsen in patients with erythromelalgia with exercise or heat exposure and may improve with cooling (24).

PATHOGENESIS

The pathogenesis of DFS involves a combination of inciting factors that coexist together: neuropathy (25), atherosclerosis (25), and impaired wound healing (26). In the setting of long-standing hyperglycemia, there is an increase in advanced glycosylation end products, proinflammatory factors, and oxidative stress which results in the demyelination of nerves and subsequent neuropathy (27,28). Single-cell RNA sequencing revealed that there is a unique subset of fibroblasts that overexpress factors associated with healing within the wound bed as opposed to the wound edge (28A). Additionally, wound healers demonstrate an increase in M1 macrophages as opposed to non-wound healers which have an increase in M2 macrophages. The effect on sensory and motor nerves, can blunt the perception of adverse stimuli and produce an altered gait, increasing the likelihood of developing foot ulcers and malformations. Also damage to autonomic nerve fibers causes a reduction in sweating which may leave skin in the lower extremity dehydrated and prone to fissures and secondary infection (29). In addition to neuropathy, accelerated arterial atherosclerosis can lead to peripheral ischemia and ulceration (30). It has been reported that diabetic patients with Charcot neuroarthropathy are associated with greater impairment of cutaneous microvascular reactivity when compared to non-complicated diabetic groups (30A). Finally, hyperglycemia impairs macrophage functionality as well as increases and prolongs the inflammatory response, slowing the healing of ulcers (31).

TREATMENT

Treatment should involve an interdisciplinary team-based approach with a focus on prevention and management of current ulcers. Prevention entails daily surveillance, appropriate foot hygiene, and proper footwear, walkers, or other devices to minimize and distribute pressure. An appropriate wound care program should be used to care for ongoing ulcers. Different classes of wound dressing should be considered based on the wound type. Hydrogels, hyperbaric oxygen therapy, topical growth factors, and biofabricated skin grafts are also available (19). The clinical presentation should indicate whether antibiotic therapy or wound debridement is necessary (19). In patients with chronic treatment resistant ulcers, underlying ischemia should be considered; these patients may require surgical revascularization or bypass.

EPIDEMIOLOGY

Scleroderma-like skin changes are a distinct and easily overlooked group of findings that are commonly observed in patients with diabetes. Ten to fifty percent of patients with diabetes present with the associated skin findings (32). Scleroderma-like skin changes occurs more commonly in those with type 1 diabetes and in those with longstanding disease (33). There is no known variation in prevalence between males and females, or between racial groups.

PRESENTATION

Scleroderma-like skin changes develop slowly and present with painless, indurated, occasionally waxy appearing, thickened skin. These changes occur symmetrically and bilaterally in acral areas. In patients with scleroderma-like skin changes the acral areas are involved, specifically the dorsum of the fingers (sclerodactyly), proximal interphalangeal, and metacarpophalangeal joints. Severe disease may extend centrally from the hands to the arms or back. A small number of patients with diabetes may develop more extensive disease, which presents earlier and with truncal involvement. The risk of developing nephropathy and retinopathy is increased in those with scleroderma-like skin changes who also have type 1 diabetes (33,34). The aforementioned symptoms are also associated with diabetic hand syndrome which may present with limited joint mobility, palmar fibromatosis (Dupuytren's contracture), and stenosing tenosynovitis (“trigger finger”) (35). The physical exam finding known as the “prayer sign” (inability to flushly press palmar surfaces on each hand together) may be present in patients with diabetic hand syndrome and scleroderma-like skin changes (36). On histology, scleroderma-like skin changes reveal thickening of the dermis, minimal-to-absent mucin, and increased interlinking of collagen. Although on physical exam scleroderma may be difficult to distinguish from these skin changes, scleroderma-like skin changes are not associated with atrophy of the dermis, Raynaud’s syndrome, pain, or telangiectasias.

PATHOGENESIS

Although not fully understood, the pathogenesis is believed to involve the strengthening of collagen as a result of reactions associated with advanced glycosylation end products or a buildup of sugar alcohols in the upper dermis (37,38).

TREATMENT

Scleroderma-like skin changes is a chronic condition that is also associated with joint and microvascular complication. Therapeutic options are extremely limited. One observational report has suggested that very tight blood sugar control may result in the narrowing of thickened skin (39). In addition, aldose reductase inhibitors, which limit increases in sugar alcohols, may be efficacious (38). In patients with restricted ranges of motions, physical therapy can help to maintain and improve joint mobility.

EPIDEMIOLOGY

Scleredema diabeticorum is a chronic and slowly progressive sclerotic skin disorder that is often seen in the context of diabetes. Whereas 2.5% to 14% of all patients with diabetes have scleredema, over 50% of those with scleredema present with concomitant diabetes (47). Scleredema has a proclivity for those with a long history of diabetes. It remains unclear whether there is a predilection for scleredema in those with type 1 diabetes (48) compared to those with type 2 diabetes (48). Women are affected more often than men (49). Although all ages are affected, scleredema occurs more frequently in those over the age of twenty (48,49).

PRESENTATION

Scleredema presents with gradually worsening indurated and thickened skin. These skin changes occur symmetrically and diffusely. The most commonly involved areas are the upper back, shoulders, and back of the neck. The face, chest, abdomen, buttocks, and thighs may also be involved; however, the distal extremities are classically spared. The affected areas are normally asymptomatic but there can be reduced sensation. Patients with severe longstanding disease may develop a reduced range of motion, most often affecting the trunk. In extreme cases, this can lead to restrictive respiratory problems. A full thickness skin biopsy may be useful in supporting a clinical presentation. The histology of scleredema displays increased collagen and a thickened reticular dermis, with a surrounding mucinous infiltrate, without edema or sclerosis.

PATHOGENESIS

Although many theories center on abnormalities in collagen, there is no a consensus regarding the pathogenesis of scleredema. The pathogenesis of scleredema may involve an interplay between non-enzymatic glycosylation of collagen, increased fibroblast production of collagen, or decreases in collagen breakdown (50,51).

TREATMENT

Scleredema diabeticorum is normally unresolving and slowly progressive over years. Improved glycemic control may be an important means of prevention but evidence has not shown clinical improvements in those already affected by scleredema diabeticorum. A variety of therapeutic options have been proposed with variable efficacy. Some of these therapies include immunosuppressants, corticosteroids, intravenous immunoglobulin, and electron-beam therapy (52). Phototherapy with UVA1 or PUVA may be effective in those that are severely affected (52). Independent of other treatments, physical therapy is an important therapeutic modality for patients with scleredema and reduced mobility (53).

EPIDEMIOLOGY

Necrobiosis lipoidica (NL) is a rare chronic granulomatous dermatologic disease that is seen most frequently in patients with diabetes. Although nearly one in four patients presenting with NL will also have diabetes, less than 1% of patients with diabetes will develop NL (54). For unknown reasons, NL expresses a strong predilection for women compared to men (55). NL generally occurs in type 1 diabetes during the third decade of life, as opposed to type 2 diabetes in which it commonly presents in the fourth or fifth decades of life (54). The majority of cases of NL presents years after a diagnosis of diabetes mellitus; however, 14% to 24% of cases of NL may occur prior to or at the time of diagnosis (56). One study evaluating comorbidities and diabetic complications in patients with NL found high rates of smoking, hypertension, hyperlipidemia, obesity, coronary artery disease, myocardial infarction, thyroid disease, poor kidney function, and poor glucose control (56A). The highest comorbidity rates in patients with NL were patients with type 2 diabetes.

PRESENTATION

NL begins as a single or group of firm well-demarcated rounded erythematous papules (figure 3). The papules then expand and aggregate into plaques characterized by circumferential red-brown borders and a firm yellow-brown waxen atrophic center containing telangiectasias. NL occurs bilaterally and exhibits Koebnerization. Lesions are almost always found on the pretibial areas of the lower extremities. Additional involvement of the forearm, scalp, distal upper extremities, face, or abdomen may be present on occasion, and the heel of the foot or glans penis even more infrequently. If left untreated, only about 15% of lesions will resolve within twelve years. Despite the pronounced appearance of the lesions, NL is often asymptomatic. However, there may be pruritus and hypoesthesia of affected areas, and pain may be present in the context of ulceration. Ulceration occurs in about one-third of lesions, and has been associated with secondary infections and squamous cell carcinoma. The histology of NL primarily involves the dermis and is marked by palisading granulomatous inflammation, necrobiotic collagen, a mixed inflammatory infiltrate, blood vessel wall thickening, and reduced mucin.

Figure 3.

Necrobiosis Lipoidica

PATHOGENESIS

The pathogenesis of NL is not well understood. The relationship between diabetes and NL has led some to theorize that diabetes-related microangiopathy is related to the development of NL (54). Other theories focus on irregularities in collagen, autoimmune disease, neutrophil chemotaxis, or blood vessels (57).

TREATMENT

NL is a chronic, disfiguring condition that can be debilitating for patients and difficult for clinicians to manage. Differing degrees of success have been reported with a variety of treatments; however, the majority of such reports are limited by inconsistent treatment responses in patients and a lack of large controlled studies. Corticosteroids are often used in the management of NL and may be administered topically, intralesionally, or orally. Corticosteroids can be used to manage active lesions, but is best not used in areas that are atrophic. Success has also been reported with calcineurin inhibitors (e.g., cyclosporine), anti-tumor necrosis factor inhibitors (e.g., infliximab), pentoxifylline, antimalarials (e.g., hydroxychloroquine), PUVA, granulocyte colony stimulating factor, dipyridamole, and low-dose aspirin (54). Appropriate wound care is important for ulcerated lesions; this often includes topical antibiotics, protecting areas vulnerable to injury, emollients, and compression bandaging. Surgical excision of ulcers typically has poor results. Some ulcerated lesion may improve with split-skin grafting. Although still recommended, improved control of diabetes has not been found to lead to an improvement in skin lesions. Patients with newly diagnosed NL should be screened for hypertension, hyperlipidemia, and thyroid disease (56A).

EPIDEMIOLOGY

Bullosis diabeticorum (BD) is an uncommon eruptive blistering condition that presents in those with diabetes mellitus. Although BD can occasionally present in early-diabetes (58), it often occurs in long-standing diabetes along with other complications such as neuropathy, nephropathy, and retinopathy. In the United States, the prevalence of BD is around 0.5% amongst patients with diabetes and is believed to be higher in those with type 1 diabetes (13). BD is significantly more common in male patients than in female patients (59). The average age of onset is between 50 and 70 years of age (59).

PRESENTATION

BD presents at sites of previously healthy-appearing skin with the abrupt onset of one or more non-erythematous, firm, sterile bullae. Shortly after forming, bullae increase in size and become more flaccid, ranging in size from about 0.5 cm to 5 cm. Bullae frequently present bilaterally involving the acral areas of the lower extremities. However, involvement of the upper extremities and even more rarely the trunk can be seen. The bullae and the adjacent areas are nontender. BD often presents acutely, classically overnight, with no history of trauma to the affected area. Generally, the bullae heal within two to six weeks, but then commonly reoccur. Histological findings are often non-specific but are useful in distinguishing BD from other bullous diseases. Histology, typically shows an intraepidermal or subepidermal blister, spongiosis, no acantholysis, minimal inflammatory infiltrate, and normal immunofluorescence.

PATHOGENESIS

There is an incomplete understanding of the underlying pathogenesis of BD and no consensus regarding a leading theory. Various mechanisms have been proposed, some of which focus on autoimmune processes, exposure to ultraviolet light, variations in blood glucose, neuropathy, or changes in microvasculature (60).

TREATMENT

BD resolve without treatment and are therefore managed by avoiding secondary infection and the corresponding sequelae (e.g., necrosis, osteomyelitis). This involves protection of the affected skin, leaving blisters intact (except for large blisters, which may be aspirated to prevent rupture), and monitoring for infection. Topical antibiotics are not necessary unless specifically indicated, such as with secondary infection or positive culture.

EPIDEMIOLOGY

Perforating dermatoses refers to a broad group of chronic skin disorders characterized by a loss of dermal connective tissue. A subset of perforating dermatoses, known as acquired perforating dermatoses (APD), encompasses those perforating dermatoses that are associated with systemic diseases. Although APD may be seen with any systemic diseases, it is classically observed in patients with chronic renal failure or long-standing diabetes (65). APD occurs most often in adulthood in patients between the ages of 30 and 90 years of age (65,66). The prevalence of APD is unknown. It is estimated that of those diagnosed with APD about 15% also have diabetes mellitus (67). In a review, 4.5% to 10% of patients with chronic renal failure presented with concurrent APD (68,69).

PRESENTATION

APD presents as groups of hyperkeratotic umbilicated-nodules and papules with centralized keratin plugs. The lesions undergo Koebnerization and hence the extensor surfaces of the arms and more commonly the legs are often involved; eruptions also occur frequently on the trunk. However, lesions can develop anywhere on the body. Lesions are extremely pruritic and are aggravated by excoriation. Eruptions may improve after a few months but an area of hyperpigmentation typically remains. Histologically, perforating dermatoses are characterized by a lymphocytic infiltrate, an absence or degeneration of dermal connective tissue components (e.g., collagen, elastic fibers), and transepidermal extrusion of keratotic material.

PATHOGENESIS

The underlying pathogenesis is disputed and not fully understood. It has been suggested that repetitive superficial trauma from chronic scratching may induce epidermal or dermal derangements (70). The glycosylation of microvasculature or dermal components has been suggested as well. Other hypotheses have implicated additional metabolic disturbances, or the accumulation of unknown immunogenic substances that are not eliminated by dialysis (65). APD is also considered a form of prurigo nodularis (70A).

TREATMENT

APD can be challenging to treat and many of the interventions have variable efficacy. Minimizing scratching and other traumas to involved areas can allow lesions to resolve over a period of months. This is best achieved with symptomatic relief of pruritus. Individual lesions can be managed with topical agents such as keratolytics (e.g., 5% to 7% salicylic acid), retinoids (e.g., 0.01% to 0.1% tretinoin), or high-potency steroids (71). Refractory lesions may respond to intralesional steroid injections or cryotherapy (71). A common initial approach is a topical steroid in combination with emollients and an oral antihistamine. Generalized symptoms may improve with systemic therapy with oral retinoids, psoralen plus UVA light (PUVA), allopurinol (100 mg daily for 2 to 4 months), or oral antibiotics (doxycycline or clindamycin) (72). Additionally, as APD is a form of prurigo nodularis, the use of immunomodulating agents such as dupilumab may be effective in treating the condition. There is evidence of dupilumab monotherapy effectively treating certain forms of APD (72A). Nevertheless, effective management of the underlying systemic disease is fundamental to the treatment of APD. In those with diabetes, APD is unlikely to improve without improved blood sugar control. Moreover, dialysis does not reduce symptoms; however, renal transplantation can result in the improvement and resolution of cutaneous lesions.

EPIDEMIOLOGY

Eruptive xanthomas (EX) is a clinical presentation of hypertriglyceridemia, generally associated with serum triglycerides above 2,000 mg/dL (73). However, in patients with diabetes, lower levels of triglycerides may be associated with EX. The prevalence of EX is around one percent in type 1 diabetes and two percent in type 2 diabetes (74,75). Serum lipid abnormalities are present in about seventy-five percent of patients with diabetes (76).

PRESENTATION

EX has been reported as the first presenting sign of diabetes mellitus, granting it can present at any time in the disease course. EX presents as eruptions of clusters of glossy pink-to-yellow papules, ranging in diameter from 1 mm to 4 mm, overlying an erythematous area (figure 5). The lesions can be found on extensor surfaces of the extremities, the buttocks, and in areas susceptible in Koebnerization. EX is usually asymptomatic but may be pruritic or tender. The histology reveals a mixed inflammatory infiltrate of the dermis which includes triglyceride containing macrophages, also referred to as foam cells.

Figure 5.

Eruptive Xanthomas

PATHOGENESIS

Lipoprotein lipase, a key enzyme in the metabolism of triglyceride rich lipoproteins, is stimulated by insulin. In an insulin deficient state, such as poorly controlled diabetes, there is decreased lipoprotein lipase activity resulting in the accumulation of chylomicrons and other triglyceride rich lipoproteins (77). Increased levels of these substances are scavenged by macrophages (78). These lipid-laden macrophages then collect in the dermis of the skin where they can lead to eruptive xanthomas.

TREATMENT

EX can resolve with improved glycemic control and a reduction in serum triglyceride levels (79). This may be achieved with fibrates or omega-3-fatty acids in addition to an appropriate insulin regimen (80). A more comprehensive review of the treatment of hypertriglyceridemia can be found in the Triglyceride Lowering Drugs section of Endotext.

EPIDEMIOLOGY

Although various forms of granuloma annulare exist, only generalized granuloma annulare (GGA) is thought to be associated with diabetes. It is estimated that between ten and fifteen percent of cases of GGA occur in patients with diabetes (96). Meanwhile, less than one percent of patients with diabetes present with GGA. GGA occurs around the average age of 50 years. It occurs more frequently in women than in men, and in those with type 1 diabetes (97).

PRESENTATION

GGA initially presents with groups of skin-colored or reddish, firm papules which slowly grow and centrally involute to then form hypo- or hyper-pigmented annular rings with elevated circumferential borders. The lesions can range in size from 0.5 cm to 5.0 cm. The trunk and extremities are classically involved in a bilateral distribution. GGA is normally asymptomatic but can present with pruritus. The histology shows dermal granulomatous inflammation surrounding foci of necrotic collagen and mucin. Necrobiosis lipoidica can present similarly to GGA; GGA is distinguished from necrobiosis lipoidica by its red color, the absence of an atrophic epidermis, and on histopathology: the presence of mucin and lack of plasma cells.

PATHOGENESIS

The pathogenesis of GGA is incompletely understood. It is believed to involve an unknown stimulus that leads to the activation of lymphocytes through a delayed-type hypersensitivity reaction, ultimately initiating a proinflammatory cascade and granuloma formation (98).

TREATMENT

GGA has a prolonged often unresolving disease course and multiple treatments have been suggested to better manage GGA. However, much of the information stems from small studies and case reports. Antimalarials, retinoids, corticosteroids, dapsone, cyclosporine, PUVA, and calcineurin inhibitors have been suggested as therapies (98).

BACTERIAL

Erysipelas and cellulitis are cutaneous infections that occur frequently in patients with diabetes. Erysipelas presents with pain and well-demarcated superficial erythema. Cellulitis is a deeper cutaneous infection that presents with pain and poorly-demarcated erythema. Folliculitis is common among patients with diabetes, and is characterized by inflamed, perifollicular, papules and pustules. Treatment for the aforementioned conditions depends on the severity of the infection. Uncomplicated cellulitis and erysipelas are typically treated empirically with oral antibiotics, whereas uncomplicated folliculitis may be managed with topical antibiotics. Colonization with methicillin-resistant Staphylococcus aureus (MRSA) is not uncommon among patients with diabetes (112); however, it is debated as to whether or not colonized patients are predisposed to increased complications (113) such as bullous erysipelas, carbuncles, or perifollicular abscesses. Regardless, it is important that appropriate precautions are taken in these patients and that antibiotics are selected that account for antimicrobial resistance.

Infection of the foot is the most common type of soft tissue infection in patients with diabetes. If not managed properly, diabetic foot infections can become severe, possibly leading to sepsis, amputation, or even death. Although less severe, the areas between the toes and the toenails are also frequently infected in patients with diabetes. Infections can stem from monomicrobial or polymicrobial etiologies. Staphylococcal infections are the most common (114), although complications with infection by Pseudomonas aeruginosa are also common (115). Pseudomonal infection of the toenail may present with a green discoloration, which may become more pronounced with the use of a Wood’s light. Treatment frequently requires coordination of care from multiple medical providers. Topical or oral antibiotics and surgical debridement may be indicated depending on the severity of the infection.

Necrotizing fasciitis is an acute life-threatening infection of the skin and the underlying tissue. Those with poorly controlled diabetes are at an increased risk for necrotizing fasciitis. Necrotizing fasciitis presents early with erythema, induration, and tenderness which may then progress within days to hemorrhagic bullous. Patients will classically present with severe pain out of proportion to their presentation on physical exam. Palpation of the affected area often illicit crepitus. Involvement can occur on any part of the body but normally occurs in a single area, most commonly affecting the lower extremities. Fournier’s gangrene refers to necrotizing fasciitis of the perineum or genitals, often involving the scrotum and spreading rapidly to adjacent tissues. The infection in patients with diabetes is most often polymicrobial. Complications of necrotizing fasciitis include thrombosis, gangrenous necrosis, sepsis, and organ failure. Necrotizing fasciitis has a mortality rate of around twenty percent (116). In addition, those patients with diabetes and necrotizing fasciitis are more likely to require amputation during their treatment (117). Treatment is emergent and includes extensive surgical debridement and broad-spectrum antibiotics.

Erythrasma is a chronic asymptomatic cutaneous infection, most often attributed to Corynebacterium minutissiumum. Diabetes mellitus, as well as obesity and older age are associated with erythrasma. Erythrasma presents with non-pruritic non-tender clearly demarcated red-brown finely scaled patches or plaques. These lesions are commonly located in intriginuous areas such as the axilla or groin. Given the appearance and location, erythrasma can be easily mistaken for tinea or Candidia infection; in such cases, the presence of coral-red fluorescence under a Wood’s light can confirm the diagnosis of erythrasma. Treatment options include topical erythromycin or clindamycin, Whitfield’s ointment, and sodium fusidate ointment. More generalized erythrasma may respond better to oral erythromycin.

Malignant otitis externa is a rare but serious infection of the external auditory canal that occurs most often in those with a suppressed immune system, diabetes mellitus, or of older age. Malignant otitis externa develops as a complication of otitis externa and is associated with infection by Pseudomonas aeruginosa. Patients with malignant otitis externa present with severe otalgia and purulent otorrhea. The infection can spread to nearby structures and cause complications such as chondritis, osteomyelitis, meningitis, or cerebritis. If untreated, malignant otitis externa has a mortality rate of about 50%; however, with aggressive treatment the mortality rate can been reduced to 10% to 20% (118). Treatment involves long-term systemic antibiotics with appropriate pseudomonal coverage, hyperbaric oxygen, and possibly surgical debridement.

FUNGAL

Candidiasis is a frequent presentation in patients with diabetes. Moreover, asymptomatic patients presenting with recurrent candidiasis should be evaluated for diabetes mellitus. Elevated salivary glucose concentrations (119) and elevated skin surface pH in the intertriginous regions of patients with diabetes (120) may promote an environment in which candida can thrive. Candida infection can involve the mucosa (e.g., thrush, vulvovaginitis), intertriginous areas (e.g., intertrigo, erosion interdigital, balanitis), or nails (e.g., paronychia). Mucosal involvement presents with pruritus, erythema, and white plaques which can be removed when scraped. Intertriginous Candida infections may be pruritic or painful and present with red macerated, fissured plaques with satellite vesciulopustules. Involvement of the nails may present with periungual inflammation or superficial white spots. Onchyomycosis may be due to dermatophytes (discussed below) or Candidal infection. Onchomycosis, characterized by subungual hyperkeratosis and oncholysis, is present in nearly one in two patients with type 2 diabetes mellitus. Candidiasis is treated with topical or oral antifungal agents. Patients also benefit from improved glycemic control and by keeping the affected areas dry.

Although it remains controversial, dermatophyte infections appear to be more prevalent among patients with diabetes (121-123). Various regions of the body may be affected but tinea pedis (foot) is the most common dermatophyte infection effecting patients; it presents with pruritus or pain and erythematous keratotic or bullous lesions. Relatively benign dermatophyte infections like tinea pedis can lead to serious sequela, such as secondary bacterial infection, fungemia, or sepsis, in patients with diabetes if not treated hastily. Patients with diabetic neuropathy may be especially vulnerable (124). Treatment may include topical or systemic antifungal medications depending on the severity.

Mucormycosis is a serious infection that is associated with type 1 diabetes mellitus, particularly common in those who develop diabetic ketoacidosis. A variety of factors including hyperglycemia and a lower pH, create an environment in which Rhizopus oryzae, a common pathogen responsible for mucormycosis, can prosper. Mucormycosis may present in different ways. Rhino-orbital-cerebral mucormycosis is the most common presentation; it develops quickly and presents with acute sinusitis, headache, facial edema, and tissue necrosis. The infection may worsen to cause extensive necrosis and thrombosis of nearby structures such as the eye. Mucormycosis should be treated urgently with surgical debridement and intravenous amphotericin B. When it is not suitable to administer amphotericin B in patients, the alternative use of new triazoles, posaconazole and isavuconazole, may be beneficial treatments (124A).

Lastly, abnormal toe web findings (e.g., maceration, scale, or erythema) may be an early marker of irregularities in glucose metabolism and of undiagnosed diabetes mellitus (125). Additionally, such findings may be a sign of epidermal barrier disruption, a precursor of infection (125).