Diabetes Mellitus

Introduction   Diabetes mellitus is a metabolic disorder characterized by a state of relative or complete insulin deficiency, leading to gross defects in glucose, fat, and protein metabolism. In type 1 diabetes (formerly insulin-dependent DM), an insufficiency of insulin (insulinopenia) occurs through a gradual, autoimmune mediated destruction of β islet cells in the pancreas. In type 2 diabetes (formerly noninsulin-dependent DM), chronic hyperglycemia occurs mainly through end-organ insulin resistance followed by a progressive decrease in pancreatic insulin release associated with aging. A fasting blood glucose level of ≥126 mg/dL or a random value of ≥200 mg/dL on two separate occasions confirms the diagnosis of diabetes. In both types of diabetes, abnormalities of insulin and hyperglycemia lead to vascular, metabolic, neuropathic, and immunologic abnormalities. Affected organs include the cardiovascular, renal, nervous systems, eyes, and the skin. ·       Vascular abnormality is related to diabetic micro and macroangiopathy. ·       Metabolic abnormalities: Obesity, insulin resistance and hyperlipidemia lead to acanthosis nigricans, skin tags and eruptive xanthomas. ·       Neuropathy, due to damaged endoneurial microvessels, leads to the diabetic foot and foot ulcers. ·       Immunological abnormality contributes to certain serious skin infections. ·       Diabetes-associated skin conditions without a known pathogenesis include: necrobiosis lipoidica, granuloma annulare, cheiroarthropathy, scleredema diabeticorum, acquired perforating dermatosis, and bullosis diabeticorum.
Diabetes is classified loosely into four types: 1.   Type 1: insulin dependent; usually juvenile onset, associated with HLA DR3, DQB1*0201 and DR4 and diabetes‐associated autoantibodies, and prone to ketoacidosis. 2.   Type 2: generally non‐insulin dependent; usually adult onset and associated with obesity. 3.   Secondary diabetes: iatrogenic or associated with pancreatic, hormonal and genetic disease. 4.   Gestational diabetes: associated with pregnancy. However, there is considerable overlap between these groups.
Cutaneous complications of diabetes ·        Infections (notably, oral and genital candidosis, Candida intertrigo, recurrent folliculitis, abscess and erysipelas) ·        Ulcers and gangrene (as secondary skin changes due to diabetic microangiopathy and neuropathy) ·        Necrobiosis lipoidica ·        Diabetic rubeosis ·        Lipoatrophy/lipohypertrophy (including post‐insulin injection) ·        Diabetic dermopathy (Binkley spots) ·        Diabetic sclerodactyly (diabetic stiff skin, diabetic cheiroarthropathy) ·        Diabetic scleredema ·        Diabetic bullae (bullosis diabeticorum) ·        Acanthosis nigricans (including its possible minor/disseminated variant, finger pebbles) ·        Carotenaemia (‘aurantiasis cutis’, xanthochromia due to β‐carotene accumulation in stratum corneum associated with diabetic hypercarotenaemia, especially over the knuckles, elbows, knees and in palmoplantar skin) ·        Acquired perforating dermatosis ·        Eruptive xanthomas ·        Generalized granuloma annulare ·        Vitiligo ·        Cutaneous adverse effects of antidiabetic agents (including phototoxic and photoallergic reactions)

Skin signs due to diabetic vascular abnormalities

 

Diabetic microangiopathy

Pathogenesis of diabetic skin microangiopathy

 

Both small and large blood vessels are affected in diabetes mellitus. In diabetic microangiopathy, there is proliferation of endothelial cells and deposits of PAS-positive material in the basement membrane of arterioles, capillaries and venules with resulting decreased luminal area. The diabetic microangiopathy is the primary expression of the disease and precedes manifestation of the disease.

 

Diabetic Dermopathy

This is the most common dermatosis associated with diabetes mellitus and is a marker for complications of diabetes such as retinopathy, nephropathy and neuropathy. About half of patients show such lesions, more frequently men than women.  The lesions are atrophic slightly depressed brownish scar predominantly situated on the shins that are asymptomatic. The lesions are possibly precipitated by trauma.

Erysipelas-like acral erythema

This condition is seen mostly in elderly diabetic patients. Well-demarcated, red areas occur on the hands or feet.

Diabetic rubeosis

Chronic, flushed rosy reddening of the face, neck and upper limb. Improved by dietary diabetic control. Flares with vasodilator therapies

 

Large vessel disease (Diabetic macroangiopathy)

 

Atherosclerosis of the large muscular arteries is about 10-20 times more common in diabetic patients and appearing 10 – 20 years earlier. Common clinical sequelae are CAD, CVA and PAD. Microangiopathy is usually present together with macroangiopathy.

 

Dry gangrene of the foot

Gangrene of the foot is estimated to be up to 150 times more frequent in diabetic than in non diabetic individuals, most often occurring in those who smoke.  PAD is responsible for diabetic gangrene. The patient shows intermittent claudication with pale and cool skin on the distal extremities. Earliest infarctive changes include well demarcated map like areas of epidermal necrosis. Later, when gangrene develops, the infarcted skin becomes mummified, dry and black (purple cyanosis → white pallor → black gangrene).

 

Leg ulceration

 

Ulceration of the leg and foot may be due to vascular and/or neurological damage. There is both structural impairment of cutaneous blood flow due to vascular damage and functional impairment, probably resulting predominantly from autonomic neuropathy.

 

Wet gangrene of the foot

In someone suffering from diabetes, sudden loss of perfusion to the already compromised cutaneous microcirculation (e.g. due to local infection or heart failure) may result in a wet necrotic area. This differs from the dry peripheral gangrene seen in arteriopathies. It is a late manifestation of diabetic microangiopathy.

 

Obesity and hyperlipidemia‐related skin disease

 

Acanthosis nigricans

Acanthosis nigricans is probably the most easily recognized skin manifestation of diabetes. Acanthosis nigricans is common in the general population, and commonly associated with insulin resistance in both adults and children. Most patients are obese.

Tissue resistance to insulin causes high plasma levels of insulin as seen in early insulin-resistant type 2 diabetes are thought to contribute to the development of acanthosis nigricans because excess insulin binding to IGF1 receptors on keratinocytes and fibroblasts, thereby stimulate their proliferation.

Clinically, acanthosis nigricans presents as velvety thickening and hyperpigmentation of the skin on the body folds such as posterolateral neck, axillae, groin, and abdominal folds as well as back of the hands over the knuckles is, most commonly seen in obese type 2 diabetic patients. The distribution is usually symmetric. In general, however, the back of the neck is the most consistently and severely affected area. The development of superimposed acrochordons in involved areas is well described.

 

Skin tags

 

Skin tags are small, soft, pedunculated lesions occurring on the eyelids, neck and axillae, often associated with obesity. They appear to be a marker for diabetes, independent of obesity and acanthosis nigricans.

 

Eruptive Xanthomas

Eruptive xanthomas present clinically as reddish-yellow papules on the buttocks and extensor surfaces of the extremities, resulting in a significant risk of pancreatitis. Although eruptive xanthomas are generally asymptomatic, there is often underlying severe hypertriglyceridemia (>1,000 mg/dL) and potentially undiagnosed diabetes. The lesions slowly resolve when the diabetes and hyperlipidemia are properly managed.

The activity of lipoprotein lipase (LPL) is directly dependent on insulin, making insulin central to the processing of triglyceride-rich chylomicrons and very-low-density lipoproteins. In insulin-deficient diabetic patients, this inability to metabolize and clear plasma lipoproteins, can lead to massive hypertriglyceridemia, manifesting in the skin as eruptive xanthomas.

 

 

Diabetes mellitus: Treatment‐related skin manifestations

 

Insulin lipodystrophy

 

Both atrophy and hypertrophy may occur even with newer synthetic insulins and analogues. Lipohypertrophy affected almost two‐thirds of patients. It is more common in patients who do not rotate the site of injection of insulin and can lead to impaired insulin absorption and poorer diabetic control. Lipoatrophy appears to be an immunological reaction. The introduction of synthetic insulin has made it much less common (in 1–2% of cases).

 

Allergic reactions to insulin

 

Localized allergic reactions to insulin and analogues include urticaria, painful nodules and granulomas.

 

Allergic reactions to oral hypoglycemic drugs

 

A wide range of drug reactions to diabetic medications has been described. Sulphonylureas are the most common culprits, particularly a disulfiram‐like reaction to chlorpropamide. Photosensitivity, pruritus, erythema multiforme, erythema nodosum, urticaria, lichenoid and morbilliform eruptions have all been described.

 

Diabetic neuropathy

Approximately 50% of those with diabetes develop a chronic, symmetrical, length‐dependent sensorimotor polyneuropathy, probably due to damaged endoneurial microvessels. It is closely related to poor glycemic control. Autonomic dysfunction and neuropathic pain are common features. Patients complain of numbness, tingling, aching and burning of the legs, which intensify in bed at night. Autonomic neuropathy impairs sweating of the legs with compensatory sweating elsewhere and edema, erythema and atrophy in advanced cases.

 

Diabetic foot

 

Diabetic charcotarthropathy typically presents as a warm, swollen and erythematous foot and ankle, which may mimic cellulitis. It is principally due to a combination of motor, sensory and autonomic neuropathy. Circulatory abnormalities, unprotected trauma and abnormal pressure points lead to dislocation and the fusion of joints, fracture and resorption of bone. The foot becomes deformed with distally displaced plantar fat pads, depressed metatarsal heads, hammer toes and pescavus. Proper foot care is essential to prevent formation of indolent perforating ulcers (‘mal perforans’).

 

Diabetic Ulcers

Foot ulcers occurring in 15% of diabetic patients and approximately 15% of diabetic patients with foot ulcers will eventually undergo a lower extremity amputation. Elderly patients with an insidious onset of the disease are especially at risk.

The etiology of diabetic ulcer formation is multifactorial. The principal risk factors for diabetic foot ulceration are duration of diabetes, poor control of HbA1c level and peripheral neuropathy; other factors are microangiopathy, PAD, and infection and most often they are combined.

A painless and slowly penetrating ulcer, usually located on pressure points and bony prominences such as sole over the metatarsal heads, the great toes and heels is suggestive of diabetic neuropathy. The ulcer is circular and punched out in shape, occurring in the middle of a callosity. Loss of temperature and pain sensation and absence of the ankle reflex is (an early sign of diabetic neuropathy) indicate a neuropathic origin. Callus formation is a sign of excessive pressure and precedes necrosis and breakdown of tissue to form ulcer and is surrounded by a ring of callus and may extend to underlying joint and bone. Complications are soft tissue infection and osteomyelitis.

 

Cutaneous Infections

Infections may be a presenting feature of diabetes, particularly type 2. Although skin infections due to staph aureus and streptococcus are common in diabetic patients, but certain serious infections, such as malignant external otitis, necrotizing fasciitis, and rhinocerebral mucormycosis, occur more frequently in diabetic patients with significant mortality.

Candida albicans infections of mouth, nail folds, genitals and skin folds are frequent in diabetics. Candidiasis may be the presenting feature of diabetes. Phimosis is a common complaint of diabetic men, and recurring candidal balano-posthitis is the usual cause.

 

Infections More common or more severe in Diabetic Patients

BACTERIA

·       Invasive group B streptococcus

·       Invasive group A streptococcus

·       Malignant external otitis

·       Necrotizing fasciitis

FUNGAL AND YEAST

·       Candida

·       Dermatophyte

·       Rhinocerebral mucormycosis

 

Pathogenesis of immune dysfunction in diabetes

Leucocyte chemo taxis, adherence and phagocytosis are impaired in patients with diabetes, especially during hyperglycemia and diabetic acidosis. Cutaneous T cell function and response to antigen challenge are also decreased in diabetes.

 

 

 

Diabetes mellitus: Disease associations and genetic syndromes

 

Reactive perforating collagenosis (folliculitis)

 

The perforating diseases are a group of skin disorders in which altered dermal connective tissue “perforates” or are eliminated through the epidermis (transepidermal elimination). The acquired perforating dermatosis is almost always associated with diabetes mellitus, often with diabetic nephropathy on hemodialysis.

Clinically, these lesions appear as pruritic, keratotic papules mainly on the extensor surfaces of the extremities. Many are follicular and a clue to the diagnosis is the presence of a central keratotic core, which is sometimes physically removed by the patient.

 

Autoimmune disease

 

Genetic risk for several autoimmune diseases overlaps, resulting in greater frequency of other autoimmune disorders in patients with type 1 diabetes. These include thyroid disease (occurring in 15–30% of patients; more commonly hypothyroidism), celiac disease (4–9%), vitiligo (4.5%) and Addison disease (0.5%) and the associated dermatological manifestations of those diseases (dermatitis herpetiformis and pretibial myxedema).

 

 

Genetic and other systemic diseases

 

Diabetes is a feature of several genetic diseases including Werner syndrome, lipoid proteinosis and autoimmune polyendocrine syndrome. It is also seen in many systemic diseases including haemochromatosis, Cushing syndrome, acromegaly and the lipodystrophies (familial partial lipodystrophy, acquired partial lipoatrophy and HIV‐associated lipodystrophy). A reduced risk of atopy has been reported in diabetes.

 

 

Disorders with Unknown Pathogenesis

 

Granulomatous disorders 

Necrobiosis Lipoidica

Necrobiosis lipoidica (NL) is a valid marker of diabetes, but it occurs only in < 1% of diabetic individuals and conversely >50% of patients with NL develops diabetes.

The mean age of onset is around 30 years, with female: male ratio: 3:1. The pathogenesis of this skin disease is unclear.  Control of the diabetes has no effect on the course of NL.

The skin lesion is a multicolored plaque. The sharply defined and slightly elevated indurated active border retains a red color, whereas the center becomes atrophic and depressed and acquires a yellow hue. Through the shiny and atrophic thin epidermis, multiple telangiectatic vessels are seen against yellow background, taking on the characteristic “glazed-porcelain” sheen. As anesthesia of the plaques occurs, ulcer may develop within the plaques due to trauma, and heals slowly to form depressed scars. Usually one to three lesions; >80% occur on the shin; at times symmetric.

Given the generally benign nature of the lesions, physicians should consider the adage “do no harm.” Focus should be on prevention of ulcers.

Granuloma Annulare

The association of GA with diabetes is weaker than that of NL. Diabetes is found more frequently in patients with adult onset GA and in those with generalized. Small grouped papules assuming an annular configuration, often in a symmetrical distribution on the trunk and extremities are seen. The pathogenesis is unclear.

 

Diabetic Thick Skin/Cheiroarthropathy

 

Hyperglycemia leads to non enzymatic glycosylation (NEG) of various proteins, including collagen. Although NEG occurs normally with aging, the process is greatly accelerated in diabetes. NEG leads to the formation of advanced glycation end products (AGEs) that are responsible for decrease degradation of cutaneous collagen. Disorders such as diabetic thick skin and limited joint mobility (LJM) are thought to result directly from accumulation of AGEs.

Diabetic LJM presents as tightness and thickening of the skin and periarticular connective tissue of the fingers, resulting in a painless loss of joint mobility. Initial involvement of the distal interphalangeal joints of the fifth digit usually progresses radially to involve all fingers. This disorder is characterized by the “prayer sign,” which is an inability to approximate the palmar surfaces of the hands and fingers with the hands pressed together and fingers separated.  In addition to flexion joint contractures, the skin may appear thickened, waxy, and smooth with apparent loss of adnexa, resembling skin changes in scleroderma. The “diabetic hand syndrome” represents a combination of LJM and the scleroderma-like syndrome.

 

Diabetic Finger pebbles

Finger pebbles are probably a variant of acral acanthosis nigricans. Patients have hundreds of grouped, tiny papules on the dorsum of hands (particularly over the knuckles and periungual area) and feet.

Scleredema Diabeticorum

It presents with the insidious onset of painless, symmetric poorly demarcated erythematous induration and thickening of the skin on the upper back and neck (‘buffalo hump’). Spreading to the face, shoulders, and anterior torso may occur. The skin retains a non-pitting, woody, peaud' orange quality. The condition is mainly seen in obese non-insulin-dependent diabetes.

The pathogenesis of scleredema diabeticorum is postulated to be increased production and deposition of extracellular matrix molecules such as glycosaminoglycans (GAGs, mainly hyaluronic acid).

 

Bullosis Diabeticorum

Salient features

 

·       A rare condition associated with diabetes mellitus

 

·       Tense blisters develop on normal-appearing skin in acral sites (feet, lower legs, hands); there is often an association with peripheral neuropathy

 

·       Histologically, intraepidermal and/or subepidermal blisters are observed

 

·       Spontaneous healing usually occurs in 2 to 6 weeks

 

Epidemiology

The exact prevalence of bullosis diabeticorum is unknown. The age of onset ranges from 17 to 84 years, with a mean age of 55 years. A 2: 1 male-to-female ratio has been reported, and it occurs more frequently in the setting of long-standing diabetes and neuropathy.

 

Pathogenesis

Although bullosis diabeticorum has been related to trauma and the microangiopathy of diabetes, little is known about its cause. Diabetic patients can develop blisters after minimal trauma, and there is reduced threshold for inducing suction blisters in these patients. There is no evidence of an infectious etiology.

 

Clinical Features

Bullosis diabeticorum is characterized by a sudden and spontaneous appearance of bullae within normal-appearing, non-inflamed skin of the distal extremities of diabetics. The most frequent locations (in decreasing order) are the feet, distal legs, hands, and forearms. Bullae are rarely seen on the trunk. The lesions are usually asymptomatic, but occasionally there is a mild burning sensation. Blisters often develop “overnight” and in the absence of known trauma. The bullae are tense and large in size up to several centimeters in diameter. They contain a clear, sterile fluid that can be more viscous than that found in friction blisters. When ruptured, oozing red erosions result which but heals without scarring.

Most patients have longstanding diabetes, but occasionally bullosis diabeticorum is a presenting sign of diabetes. It is associated with both insulin-dependent and non-insulin-dependent diabetes mellitus. Many patients have an associated polyneuropathy, retinopathy or nephropathy.

 

Pathology

The histologic findings are heterogeneous. Initial reports described intraepidermal blisters, whereas recent publications have usually described subepidermal bullae. It has been suggested that the level of cleavage is subepidermal, and that intraepidermal blisters represent older lesions undergoing re-epithelialization. Direct immunofluorescence (DIF) examination is usually negative, although one report described IgM and C3 deposits within dermal blood vessel walls. By electron microscopy, subepidermal blisters with a separation at the level of the lamina lucida or below the lamina densa have been described.

 

Differential Diagnosis

In porphyria cutanea tarda (PCT) and pseudoporphyria associated with dialysis and medications, the blisters are usually <1 cm in diameter and favor the hands rather than the feet and ankles. Complications of diabetes include both chronic renal failure and atherosclerotic cardiovascular disease and, as a result, patients may be receiving dialysis and/or diuretics. The distal extremity is also a common site for fixed drug eruptions, but the bullae develop on an inflammatory base. Localized bullous pemphigoid and epidermolysis bullosa acquisita (EBA) are differentiated by histologic examination and DIF, as well as by an accentuation of lesions at sites of friction in patients with EBA. If there is surrounding erythema, warmth and tenderness, the possibility of bullous cellulitis must be considered.

 

Treatment

Most patients have spontaneous healing of their lesions within 2 to 6 weeks. Treatment focuses on aspiration of blisters or placement of a small window in the blister roof and application of topical antiseptics or antibiotics to reduce discomfort and prevent secondary infections, respectively. Occasionally, a secondary soft tissue infection does develop, requiring systemic antibiotics or surgical intervention.