EPIDEMIOLOGY OF SKIN LESIONS IN

DIABETES MELLITUS
Numerous skin lesions are associated with either type
1 or type 2 diabetes mellitus, specific chronic
complications of the disease, use of antidiabetic drugs,
and certain endocrine and metabolic disorders that
cause secondary diabetes mellitus.
CLASSIFICATION OF DERMATOLOGIC
LESIONS IN DIABETES MELLITUS
There is considerable uncertainty about the
pathogenesis of the many cutaneous conditions
affecting diabetic patients in no small part because of
our inadequate understanding of the metabolic basis of
diabetes mellitus itself.
There is no strict classification of skin lesions related
to diabetes mellitus, therefore grouping them under
the following headings will give us an idea about
various types of skin lesions occurring in diabetes. So,
one would know what are the dermatologic conditions
occurring in a diabetic (1).
Dermatologic lesions associated with but not
specific for diabetes mellitus (disease markers)
Pruritus
Necrobiosis lipoidica diabeticorum
Granuloma annulare
Diabetic dermopathy
Scleroderma-like syndrome
Acanthosis nigricans
Diabetic bullae
Skin alterations due to diabetic complications
Diabetic foot
Cutaneous infections associated with diabetes
- furunculosis
- carbuncle
- pyodermas
- candidiasis
- dermatophytosis
Erythrasma
Xanthomatosis
Xanthelasma
Pycomycetes
Malignant otitis media
Dermatologic changes associated with
neurovascular complications
Macroangiopathy
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Diabetologia Croatica 31-3, 2002
1
Pathuri Skin Hospital,
Near Gokawaram Bus Stand
Rajahmundry
Andhra Pradesh, India
2
Vuk Vrhovac Institute, University Clinic for Diabetes,
Endocrinology and Metabolic Diseases,
Dugi dol 4a, HR-10000 Zagreb, Croatia
Review
DERMATOLOGIC LESIONS IN DIABETES MELLITUS
Chilukuri Sreedevi
1
, Nikica Car
2
, Ivana Pavli-Renar
2
Microangiopathy
Diabetic neuropathy
Dermatologic complications of diabetes
treatment
with oral hypoglycemic drugs
with insulin
Endocrine syndromes with skin alterations and
diabetes mellitus
Migratory necrolytic erythema in glucagonoma
Dermatoses that are more common in diabetes
mellitus
Perforating dermatosis
Vitiligo
Lichen planus
Eruptive xanthomas
Kaposis sarcoma
Bullous pemphigoid
Dermatitis herpetiformis
Psoriasis
VARIOUS TYPES OF DERMATOLOGIC
LESIONS IN DETAIL
Dermatologic lesions associated with but not
specific to diabetes mellitus (disease markers)
Pruritus
Generalized pruritus was once considered a typical
symptom of diabetes but its frequency is unknown.
Studies have failed to provide a statistical basis for this
belief (2,3). A higher rate of pruritus is found in liver
diseases, uremia, parasitic infestation, endocrine
disorders (thyroid), malignant diseases, hemotologic
and metabolic diseases, and as a side effect of some
drugs. Generalized pruritus is associated with diabetes
complications of chronic renal insufficiency,
occasionally neuropathy (irritation of nerve endings can
be the cause). High levels of urea in the blood cause
the skin to itch. Candidiasis or dermatophytosis may
underlie pruritus in diabetic patients. Anogenital
pruritus is often caused by candidiasis in diabetic
patients (4).
Some fungal infections most commonly occurring in
diabetics are jock itch, athletes foot and ringworm.
Jock itch appears as a red, itchy area that will spread
from genitals outward over the inside of the thighs.
Jock itch is more common in men than in women.
When athletes foot occurs the skin between the toes
will become itchy and sore. It may also crack, peel or
blister. Ringworm is identified by ring-shaped, red scaly
patches that can itch or blister. Ringworm can appear
on the feet, groin, trunk, scalp or nails. Itching in the
legs in elderly diabetics is not a feature of
hyperglycemia but rather a manifestation of xerosis.
Simple lubricants and low potency corticosteroid
application should prove helpful.
Necrobiosis lipoidica diabeticorum
The disease is very rare, occurring in 7% of diabetic
patients (5). These relatively asymptomatic lesions
are three times more common in women than in men.
It is one of the cutaneous markers of diabetes. At the
time of diagnosis 10% of the people will develop
diabetes within 5 years or have abnormal glucose
tolerance or history of the disease in at least one parent
(6). The condition occurs at any age but it generally
favors young adults at a mean age of 34 years. In insulin
users, the onset is considered to occur much earlier
than in type 2 diabetics or nondiabetics (7). The
lesions are characteristically found on the anterior and
lateral surfaces of lower legs, i.e. in the pretibial and
medial malleolar region. They may also be present on
the face, arms and trunk. There may be one or several
lesions, either unilateral or bilateral. The lesion begins
as a small, dusky-red elevated nodule with a sharply
circumscribed border. It slowly enlarges to turn into a
plaque of irregular outline, flattened, and eventually
depressed as the dermis becomes more atrophic.
The color turns more brownish-yellow except for the
border, which may remain red. Coalescing or enlarging
lesions may in time encompass the entire anterior
tibial area. The epidermis is smooth or slightly scaly
and atrophic. Delicate vessels can be seen through the
surface. The lesions may be anesthetic or have
reduced sensation to pin prick and to fine touch due to
destruction of cutaneous nerves (8).
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The chronic lesions of necrobiosis lipoidica
diabeticorum (NLD) are indolent; shallow, often
painful ulcers frequently appear in long-standing
lesions. In the early stages, NLD may resemble
granuloma annulare or sarcoid, but a well-developed
plaque is characteristic and easily recognized. The
primary pathologic changes are in the lower dermis,
where collagen is markedly altered with focal areas of
loss of normal structure, swelling, basophilia, and
distortion of the bundles (necrobiosis). Cross-striations
and diameters of collagen fibers are irregular. Although
the amount of collagen is actually decreased, the
relative proportions of types I and III are preserved.
Fibroblasts cultured from skin lesions have been
reported to produce less collagen. There is also the
loss and fragmentation of elastic fibers. There is
increased collagenase in the lesional skin. In these
areas, there are aggregations of inflammatory cells. The
late appearance of foam cells accounts for the
designation lipoidica.
The vasculature is always involved, with endothelial
proliferation and occlusion of the lumina of arterioles
and venules (9,10). Capillary walls are thickened with
focal deposits of PAS-positive material that may also
be present in the lumen. The nature of the association
with diabetes and its pathogenesis remains unclear.
Because NLD occurs in both IDDM and NIDDM, its
pathogenesis cannot be related to genetic factors,
underlying autoimmune disease, or other causes of
diabetes. It can be reasonably assumed that the
granulomatous response is secondary to alterations in
dermal collagen. It is not clear whether this is
secondary to an underlying vascular disease or
develops independently. The latter would ascribe the
changes in dermal collagen and vasculature to some
primary disorder of connective tissue (as yet
unknown). However, the invariable presence of
arteriolar changes deep into and within the areas of
collagen degeneration suggests an interrelation
between the two components of NLD (11). It has been
hypothesized that increased platelet aggregation may
be a trigger factor in vascular changes (12).
Immunoglobulins, complement (C3 and C4) (13), and
fibrinogen are present in blood vessels in lesional and,
in some cases, nonlesional skin (14). These findings
are in concordance with the presence of inflammatory
changes in adjacent clinically normal skin. The
treatment of NLD is not very satisfactory. Progression
of lesions does not correlate with normalization of
hyperglycemia. Local therapy with topical application
of glucocorticoids under occlusion or by intralesional
injection may afford some improvement of active
lesions. There have been some enthusiastic reports on
the use of aspirin and dipyridamole, but these were
not confirmed in a rigorous double-blind trial (15).
Favorable effects were obtained with very small doses
of aspirin: 3.5 mg/kg every 48 to 72 h (16). Other
helpful agents are clofazimine, nicotinamide, and
pentoxifylline. Ultraviolet light treatment has been
found to control this condition when it is flaring.
Granuloma annulare
It is a benign necrobiotic condition associated with
lesions similar to NLD, the only difference being the
absence of epidermal atrophy. This is a skin disease
usually seen in children and young adults. It is
occasionally associated with diabetes. Skin signs are
characterized by red spots in the initial stages that
expand outwards in a ring-like fashion. The hands,
especially the fingers, on dorsal or lateral aspect of the
hands and elbows (forearms), are commonly affected.
When granuloma annulare is widespread it may be
associated with underlying diabetes mellitus. The skin
lesions may precede the symptoms and signs of
diabetes mellitus. Patients with widespread granuloma
annulare need to be screened for diabetes mellitus.
Mostly it is asymptomatic and resolves spontaneously.
Diabetic dermopathy
It is the most common skin lesion occurring in
diabetics (17). It is prominent in males who are more
than 50 years of age (18). It is seen even in euglycemic,
endocrine diseases and also in healthy individuals. The
presence of small blood vessel changes has led to the
term diabetic dermopathy (17).The lesions are
asymptomatic, irregularly shaped patches occurring
primarily over the anterior lower legs; their surfaces are
depressed and they have a light brown color. The
pigmentation is due to deposition of hemosiderin in
histiocytes and extravasated superficial erythrocytes.
These lesions can occur on upper arms, thighs, and any
bony prominences. Lesions appear in crops and
gradually resolve over 12 to 18 months. The disorder is
asymptomatic requiring no treatment except for
protecting the area from any trauma and secondary
infection. Use of bio-occlusive dressing is recom-
mended.
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Scleroderma-like syndrome, reduced joint mobi-
lity, waxy skin syndrome
These terms are synonymous denoting one and the
same skin disorder (17,19). As many as one third of
diabetic patients (both IDDM and NIDDM) have
tight, thickened waxy skin over the dorsum of the
hands. Reduced joint motion probably is the earliest
complication of diabetes mellitus, a characteristic
finding in children and adolescents after only 10 years
of diabetes duration. The metacarpophalangeal and
proximal intraphalangeal joints are usually first
involved. Reduced extension, initially active, then also
passive, is observed. Flexion may for long remain
completely preserved. Clinical signs include impossible
extension of the palm on the table and impossible
clasping hands as in prayer. Restriction of passive
extension of the interphalangeal and metacarpo-
phalangeal joints is most important from the diagnostic
point of view (20,21). The skin becomes thickened,
with a waxy appearance, in about one third of patients
(22). Such skin resembles sclerodermic skin.
Histologically, dermal collagen thickening and elastic
fiber reductions are observed (23,24). This cutaneous
manifestation can accompany MODY and is considered
to be associated with poor prognosis in terms of
prediction of retinopathy and nephropathy (25,26).
However, there are no substantial evidence supporting
the above concept (27).
Acanthosis nigricans
This disorder is characterized by velvety
papillomatous hyperplasia of the disease, and diabetes.
Mild forms also occur in obesity without evident
endocrine disorder. It appears likely that a common
pathogenetic mechanism accounts for acanthosis
nigricans linked to endocrinopathy. Studies of patients
showed the epidermis with intense hyperpigmen-
tation, which was most pronounced in the axillary,
inguinal, and inframammary folds, and in the creases of
the neck.
In more severe forms it may be more generalized and
accompanied by verrucous patches on knuckles and
other extensor surfaces, hyperkeratosis of the palms
and soles, and other hyperplastic lesions. Acanthosis
nigricans is associated with two types of disorders. The
more severe form is usually found in patients with
advanced malignant disease. The more limited form is
more frequently found in association with a variety of
endocrinopathies (28), including acromegaly, Cushings
syndrome, and polycystic ovary. A variety of endocrine
diseases and acanthosis nigricans suggest that insulin
resistance is a common denominator even in the
absence of overt diabetes. It was first shown to be
associated with insulin resistance in patients with the
rare syndrome of lipoatrophic diabetes (29). Subse-
quently, acanthosis nigricans has been associated with
all three types of insulin resistance:
- type A, in which insulin resistance is due to receptor
defects resulting in decreased insulin binding;
- type B, in which insulin resistance is conferred by
effects of circulating antireceptor antibodies; and
- type C, in which postreceptor defects including
abnormalities in signal transduction such as
autophosphorylation of the receptor and activation of
tyrosine kinase inhibit insulin action (1,30).
Histologic examinations reveal marked
hyperkeratosis and papillomatous lesions (31),
although the epidermis is mildly acanthotic, i.e.
thickened (32). The use of keratolytic agents such as
salicylic acid can improve the appearance
cosmetically, if desired.
Diabetic bullae
Diabetic bullae are very rare but characteristic of
diabetes mellitus. They occur in adult males. The
bullae appear spontaneously, commonly in the dorsum
and sides of the lower legs, especially feet. Sometimes
they are associated with similar lesions on the forearm
and hands. Bullae may range from millimeters to few
centimeters. The lesions are often bilateral, containing
clear sterile fluid. There is no surrounding erythema.
Generally, the bullae heal in several weeks without
significant scarring, although they may recur (33).
These blisters are not the result of trauma or infection
(34). The bullae are subepidermal, and ultrastructural
studies have demonstrated the plane of separation to
be in the basement membrane zone above the basal
lamina. In some cases the distribution of lesions in light
exposed areas suggests porphyria cutanea tarda, but
abnormalities of porphyrin metabolism have not been
found. Neither trauma nor immune mechanisms have
been implicated. The cause of this rare manifestation
of diabetes is unknown. At least 75 percent of patients
have significant diabetic retinopathy, and in one series
of three patients dermopathy and cutaneous angio-
pathy were present (17). The localization of the plane
of separation suggests that weakness in the basement
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membrane zone is an underlying factor. That this may
be the case is suggested by the presence of a reduced
threshold to formation of suction blisters on the
forearms of insulin-dependent diabetics (35). Usually
they do not require any treatment apart from
prevention of secondary infection which can be done by
the application of bio-occlusive dressings.
Skin alterations due to diabetic complications
Neurovascular and ischemic changes and foot
ulceration (diabetic foot)
Diabetic foot is a serious complication which results
from confluence of multifactorial pathogenic
mechanisms. Neuropathy (motor, sensory and
autonomic) and diabetic angiopathy are the
contributing factors for its development, the
neuropathy being the major factor. Laceration which
may be complicated with necrosis, gangrene and
osteomyelitis, accentuated plantar arches and hammer
toes with interdigital maceration leading to bacterial
and fungal infections, and loss of the ankle jerk and
vibration sensation are the features of the diabetic foot.
Because of its serious nature it requires special
attention. Prevention is by far more relevant than cure.
Hence care of the foot must become a routine in
diabetic patients.
Cutaneous infections associated with diabetes
Poorly controlled or undiagnosed diabetics have a
greater susceptibility to bacterial and fungal infections
of the skin. The most frequently encountered
infections are staphylococcal pyodermas such as
furunculosis and carbuncles, candidiasis, erythrasma
and dermatophytosis.
Furunculosis (boils). The word boil has been derived
from the German language and refers to swelling,
There is extended involvement of the hair follicle
including the perifollicular region in the dermis and
subcutaneous tissue, i.e. there is folliculitis as well as
perifolliculitis. It is caused by Staphylococcus (S.) aureus.
Boils are common during adolescence and early adult
age. In India these are more common during the rainy
season. Isolated furuncles appear, and many lesions
may develop together. In other cases crops of lesions
keep appearing. Generally, the subjects are healthy but
have poor hygiene or are carriers of S. aureus. Factors
like diabetes mellitus, exfoliative dermatitis and intake
of systemic steroids may be responsible for their
increased frequency and greater severity.
A furuncle usually begins as a tender area, which
rapidly develops into an inflammatory indurated
nodule of 2 to 3 cm in diameter. Within the next few
days the area becomes necrotic and discharges pus from
a point at the follicular opening. Those furuncles,
which do not discharge on the surface are called blind
boils.
Carbuncle. A carbuncle may be said to be a group of
boils which show deep infection of contiguous follicles
with S. aureus. The infection spreads from one follicle
to the other usually not via the surface but through the
subcutaneous tissue. The lesion starts as a painful,
tender, firm to hard indurated lump with a course
similar to but more protracted than that of a furuncle.
It is associated with intense inflammatory changes in
the surrounding and underlying tissues. Pus is
discharged not necessarily through the follicular
openings but from any point. The common sites are the
back of the neck, shoulders, hips and thighs. It is
frequently associated with diabetes mellitus. If the
underlying conditions are controlled and appropriate
therapy instituted, healing takes place leaving a scar,
otherwise toxemia and even death may follow.
Pyodermas. The advent of antibiotics and tighter
control of diabetes has markedly reduced the incidence
and morbidity of pyodermas which were formerly
considered as serious complications. Lower extremities
constitute a particular hazard for the diabetic patient.
The associated atherosclerosis and peripheral neuro-
pathy lead to ulceration and gangrene as well as poor
wound healing.
Candidiasis (monoliasis). Candida albicans is a common
complication in poorly controlled diabetics (36). They
show considerable improvement when diabetes is
controlled. Candidal infections of the skin may
resemble those caused by other dermatophytes but are
most common where the skin is moist and in contact
with itself, e.g. groins, perineum, breasts, axillae. Nail
infections start at the base, forming ridges, often
accompanied by paronychia. Paronychia is the infection
of the web space between the middle and fourth finger.
In the mouth, white curd-like patches are seen, which
can be scraped away leaving a bleeding base (37).
Atrophy of the gums and angular stomatitis are
common in the elderly.
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Vulvovaginal candidiasis. It commonly presents with
itching, soreness, and a thick creamy white discharge.
In severe cases, there is beefy red erythema of the
vaginal mucosa and vulval skin with curdy white flecks
of discharge. The lesion may spread to the perineum
and groins. The perianal area is often affected.
Candidal vulvovaginitis may be chronic and recurrent.
Factors that predispose to candidal vaginitis include
pregnancy, diabetes mellitus, oral contraceptive or
antibiotic administration, and occlusive tight fitting
garments (38).
Balanitis or balanoposthitis. Balanitis is common among
the elderly and uncircumcised patients. Balano-
posthitis usually presents with itching, pain, erosions,
cracks and whitish scales on the terminal portion of the
prepuce. Diabetes mellitus is often the underlying
disease. In diabetic or immunosuppressed patients, a
severe edematous, ulcerative balanitis may occur.
Phimosis has been observed as a common complaint in
diabetic men and recurring candidal infection is usually
the cause.
Investigations: The yeast may be identified micro-
scopically or by culture from swabs or scrapings from
the lesions, and be cultured from the blood in systemic
disease. Underlying local or systemic defects should be
sought.
Management: Most important is to correct or control
the underlying predisposition. Cutaneous candidiasis is
treated with a topical azole ointment. Mucosal
infection usually responds well to lozenges or
suspension of nystatin or amphotericin. Persistent
infections and nail infections require oral fluconazole or
itraconazole. Systemic infections should be treated
with intravenous amphotericin or with amphotericin
plus flucytosine.
Dermatophytosis (tinea infections) ringworm infections. It is
encouraged by the sharing of wash places and ringworm
is due to the infection by dermatophyte fungi. There
are three main genera: Trichophyton (skin, hair, and nail
infections); Microsporum (skin and hair), and Epuler-
mophyton (skin and nails).
Clinical features: These depend upon the site and the
species of fungus involved.
Tinea pedis (athletes foot). This is the most common
type of fungal infection in humans. The sharing of wash
places and swimming pools encourages it. Infrequent
washing of socks and the use of occlusive footwear
encourage relapses. It may present in three main ways:
soggy interdigital scaling, diffuse powdery scaling of
the soles (which is often unilateral and which picks out
skin creases), and recurrent bouts of vesiculation of the
soles. The organisms involved are usually T. rubrum, T.
mentagrophytes var. interdigitale and E. floccosum.
Tinea unguium (tinea of the nails). Toe nail infection is
more common than finger nail infection and is often
accompanied by tinea pedis. Usually only a few nails
are infected. The changes first occur at the free edge
of the nail, which becomes yellow and crumbly.
Thickening of the nail and separation of the nail from
the nail bed may follow. T. rubrum is a frequent cause.
Tinea manuum (tinea of the hands). It is usually
asymmetric and involves the palms (dry, powdery
scaling picking out the creases) more often than the
backs of the hands.
Tinea cruris (tinea of the groin). It affects men more than
women and causes well-demarcated redness and
peripheral scaling of the groins and upper thighs. A few
vesicles or pustules are usually seen within the lesions.
The eruption is often unilateral or asymmetric, and
itchy.
Tinea corporis (tinea of the trunk). It is the archetypal
ringworm eruption. Erythematous scaly plaques
expand slowly and clear in the center, leaving a ring-
like pattern. Peripheral scaling, a few vesicles and
pustules are characteristic.
Erythrasma
As the name suggests the initial lesions are reddish
(in fact, reddish-brown) but as the disease is
asymptomatic, patients are not generally observed at
this stage. After a period of time, the lesions become
brownish-black (like a silver nitrate stain) with
irregular but very well defined borders. They are
smooth but later appear creased and even finely scaly.
The sites of predilection of clinical disease are the
genitocrural folds, axillae and submammary regions.
The Coryneforms causing erythrasma are seen in large
sections of the population in the interdigital web
spaces where they produce only mild scaling. The
lesions fluoresce coral-red under Woods light or
ultraviolet-A (UVA) light, due to coproporphyrin III
production by the bacteria. If the patient has recently
taken a bath, the fluorescence may not be observed as
the porphyrin is soluble in water.
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Xanthomatosis
Eruptive xanthomas are a characteristic but
uncommon complication of diabetes mellitus asso-
ciated with a more sustained hyperlipidemia affecting
plasma triglycerides and cholesterol more than
phospholipids, and hyperglycemia with glycosuria. The
decreased lipoprotein lipase activity in insulin-
dependent diabetics results in the accumulation of
serum triglycerides, whose levels are occasionally
highly elevated to produce eruptive xanthomas.
Cutaneous xanthomas result from deposition of lipid
in the histiocytes in the dermis or subcutaneous tissue.
Xanthomas tend to appear rapidly in crops as multiple,
small, reddish-yellow nodules of up to 0.5 cm in
diameter. They present in clusters primarily on the
extensor surfaces and buttocks. The lesions are much
smaller and more inflammatory than tendinous and
tuberous xanthomas, which are associated with
hypercholesterolemia and may be pruritic initially.
Rapid regression of these lesions occurs when
hyperlipidemia is brought under control.
Xanthelasma
It occurs in most hyperlipidemic states including
diabetes. It does not regress with therapy for diabetes.
A yellowish discoloration of the skin of the palms, soles
and nasolabial folds due to the deposition of carotene
present in excess quantities in plasma may be
associated with hyperlipidemia even in the absence of
xanthomatosis in diabetes.
Phycomycetes infection
Sometimes hyperglycemia may permit organisms that
are nonpathogenic to produce infection in traumatized
skin, which may lead to gangrene and loss of the limb.
There are various factors, which help the
phycomycetes establish and lead to the infection.
These factors include pre-exsisting leg ulcers,
nonhealing surgical wounds, deep seated fungal
infections, etc. Treatment must be aggressive,
consisting of correcting acid-base balance, debride-
ment of devitalized tissue, and intravenous antifungal
therapy. Patients with uncontrolled diabetes mellitus
and ketosis may be predisposed to deep fungal
infections or rhinocerebral mucormycosis of the
turbinates, septum, palate, maxillary and ethmoid
sinuses (38).
Malignant otitis media
It is caused by Pseudomonas aeruginosa. It is an
uncommon but a very serious infection. Initially there
is purulent discharge and pain in the external ear canal.
It occurs commonly in diabetic men. It begins as a
cellulitis and can progress to chondritis, ostomyelitis,
and infective cerebritis. It usually has fatal outcome.
So, the treatment includes the use of antipseudomonas
antibiotics and debridement of devitalized tissue if
necessary (38).
Dermatologic changes associated with
neurovascular complications of diabetes
Macroangiopathy
Patients with diabetes mellitus have a slightly higher
incidence and prevalence of large-vessel disease
compared with control subjects (39). In patients with
IDDM or NIDDM, both low-density lipoprotein
cholesterol and VLDL triglycerides are risk factors
(40). Atherosclerosis of the arteries of the legs results
in skin atrophy, hair loss, coldness of the toes, nail
dystrophy, pallor on elevation, and mottling on
dependence (33). A reliable sign of large vessel disease
is dependent rubor with delayed return of color (>15
seconds) after pressure has been applied to the skin
(41).
Microangiopathy
The role of diabetic microangiopathy is not
completely understood. The signs include diabetic
dermopathy, pigmented purpura, erysipelas such as
erythema, NLD, periungual telangiectases, and
diabetic foot (42). Other signs of microangiopathy
include cutaneous reactive hyperemia and reduced
capillary flow on cold or warm challenges of patients
with IDDM and those with NIDDM, as measured by
laser Doppler flowmetry (43-47).
The thickening of the vessel walls, perivascular
deposition of material reactive with periodic acid-
Schiff stain, and clumping of the elastic fibers in the
papillary dermis are produced by a combination of
intimal hyperplasia and increased deposition of type IV
collagen within and around the vessel wall. The space
between the pericytes and the endothelial cells is
wider, and the cytoplasmic process that formed the
contact point between them is longer and thinner than
normal, suggesting a possible explanation for increased
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permeability (48). The capillary leakage leads to the
loss of albumin and water, and the platelets have a
higher tendency to aggregate. As a result, increased
whole blood and plasma viscosity creates a sluggish
microcirculation (41).
Diabetic rubeosis is a peculiar rosy reddening of the face,
sometimes of the hands and feet, which may be
observed in longstanding diabetics. It has been
attributed to diabetic microangiopathy or a decreased
vascular tone.
Diabetic neuropathy
Elderly patients in whom the onset of diabetes is
insidious are especially at risk of developing diabetic
neuropathy. A common neuropathy in diabetes mellitus
is a distal, symmetric, mixed polyneuropathy involving
both the motor and the sensory nerves (49).
The skin manifestations of autonomic neuropathy in
diabetes mellitus are disturbances in sweating and
peripheral hyperemia with erythema, edema, and
atrophy. Motor neuropathy of the feet leads to
imbalance between flexor and extensor muscles,
displacement of fat pads, and subluxation of digits
(50).
Typical signs of sensory neuropathy in diabetes
mellitus are paresthesias with the loss of temperature
and pain sensation, as well as aching and burning of the
legs that are worse at night. The combination of motor
and sensory neuropathy along with mechanical factors
and microangiopathy plays a major role in the
development of the diabetic foot (42).
Immunohistochemical studies of nerves in diabetic
skin have demonstrated depletion of neuropathies.
The antidepressant drugs such as desipramine and
amitriptyline that inhibit the membrane pump
mechanism for the reuptake of neuropeptides have
proved effective in diabetic peripheral neuropathy
(50).
Dermatologic complications due to the treatment
of diabetes
Oral hypoglycemic drugs
The cutaneous complications of oral hypoglycemic
agents are few. They occur more commonly with first
generation sulphonylureas such as chlorpropamide and
tolbutamide, and usually develop in the first two
months of treatment. They may be either toxic or
allergic in nature.
Phototoxic reactions presenting as excessive sunburn
after exposure to sunlight occur in a few patients (52).
Allergic skin reactions are uncommon and are similar
for all hypoglycemic drugs belonging to the
sulphonylurea group. They are usually mild and self-
limited. Patients may present with intermittent or
persistent pruritus or a maculopapular rash. Other
cutaneous reactions which may occur occasionally
include urticaria and erythema multiforme, which may
progress to the Stevens-Johnson syndrome. Other rare
skin manifestations include erythema nodosum and
purpura as well as exacerbation of porphyria cutanea
tarda and generalized hypersensitivity reactions.
The chlorpropamide alcohol flush occurs in patients
taking this drug. The reaction usually begins within 15
min after ingestion of alcohol. It causes flushing,
headache, tachycardia and dyspnea that gradually
subsides after an hour. Second generation sulpho-
nylureas, which are now widely used, produce fewer
cutaneous side effects. The allergic skin reactions to
suphonylureas often disappear while the patient is
receiving a maintenance drug regimen.
Insulin
Cutaneous complications due to insulin therapy used
to be common before the advent of newer insulins.
Allergic reactions to insulin may be immediate or
delayed. Serious generalized reactions such as urticaria
and anaphylaxis are rare. The immediate local reaction
is probably IgE-mediated. It starts as erythema,
becomes urticarial within 30 min and subsides within
an hour. The delayed reaction is the most common
reaction. It is due to delayed hypersensitivity. About 2
weeks after the initiation of insulin therapy, a pruritic
nodule develops within 1 or 2 days at the site of
injection, lasts for days and heals with hyper-
pigmentation and scarring. Localized induration,
ulceration and scar formation, cutaneous abscess
formation and development of keloids may result from
faulty injection techniques. Idiosyncratic reactions are
very rare and include pigmentation and occasionally
keloid formation. Skin reaction resembling acanthosis
nigricans has been reported.
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Lipoatrophy. Insulin lipoatrophy and lipohypertrophy,
which are the complications of insulin injection, are
rare after the introduction of newer insulins.
Lipoatrophy presents as circumscribed atrophic
plaques showing atrophy of the subcutaneous fat at the
site of insulin injection, and rarely shows complete
resolution. It may be due to a local immune response to
insulin injection (53).
Lipohypertrophy. It presents as a soft dermal nodule.
The overlying skin appears normal at the site of
injection. It may be due to the lipogenic action of
insulin.
Insulin edema. Edema of the abdomen and legs is a
more common and usually a self-limiting complication
which appears shortly after starting or increasing the
dose of insulin. It is commonly seen in women (54) and
is unrelated to cardiac or renal disease. The
pathogenesis is unclear. Ephedrine is the drug of choice
(55).
Endocrine syndromes with skin alterations and
diabetes mellitus
Glucagonoma
It is the most characteristic endocrine syndrome
manifesting with skin alterations and diabetes mellitus.
This syndrome is often diagnosed late and mostly by a
dermatologist. The dermatosis is the presenting clue.
The syndrome is usually caused by tumors of the alpha-
cell, glucagon secreting portion of the pancreas. It has
four components:
- hypersecretion of glucagon,
- diabetes that is usually mild,
- weight loss, and
- necrolytic migratory erythema.
The chronic, fluctuating dermatosis is characterized
by an annular and figurative erythema that forms bullae
and erosions. The periphery of these lesions extends
with vesiculopustules. The lesions tend to coalesce
before healing which starts within weeks, as they are
replaced by new ones. They commonly occur in the
intertriginous areas, perioral regions and on ex-
tremities. Histologically, they resemble pustular pso-
riasis, with features of intracellular edema in the upper
epidermis, acanthosis and subcorneal pustulosis (56).
Necrolytic migratory erythema resolves after ex-
tirpation of the pancreatic tumor, which in the majority
of cases is the treatment of choice (57).
Dermatoses reported to be more common in
diabetics than in nondiabetics
Kaposis sarcoma
It is a multiple idiopathic hemorrhagic sarcoma,
which manifests primarily as multiple vascular nodules
in the skin and other organs. It predominantly affects
males. The lesions begin in the legs as multiple, purple
macules, nodules or plaques. Later, other areas of the
skin, mucous membranes and internal organs may be
involved. Edema of the legs is frequent and may even
be a prodrome. Histologic picture reveals accumulation
of spindle cells forming vascular slits containing
erythrocytes (58). Diabetes mellitus has been reported
with greater than expected frequency in classic
Kaposis sarcoma, however, confirmation is still needed
(59).
Perforating dermatosis
There are several acquired cutaneous disorders
having as a common histologic denominator the
transepidermal elimination of degenerative material,
chiefly collagen and elastic fibers. Many are seen in
patients with chronic renal failure, particularly those on
dialysis and with IDDM or NIDDM. The size of these
papules ranges from 2 to 10 mm in diameter, often with
a keratotic plug. They favor the extensor surface of the
trunk and extremities, and are itchy with little
tendency to spontaneous resolution. Most patients are
middle aged, often black, and more often men than
women. Improvement of itchy lesions is not achieved
easily but topical retinoic (60) and ultraviolet therapy
(61) has been useful.
Vitiligo
It is a disease with a diminished or absent function of
melanocytes resulting in macular depigmentation. It is
found mostly in periorifacial regions and also on the
extensor aspect of the extremities. It is asymptomatic
but emotionally stressful, particularly in people with
dark skin. Vitiligo occurs with a greater incidence than
expected (4.8%) in patients with maturity onset
diabetes (62) and type 2 diabetes (63). It has also been
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reported in association with IDDM and other
autoimmune disorders of the adrenal and thyroid or
gastric parietal cells.
Lichen planus
An increased incidence of diabetes mellitus and
abnormal insulin response to glucose challenge have
been claimed in patients with lichen planus (64). This
seems particularly so in adults, especially those with
the erosive oral form (65). There were various studies
of lichen planus and its relationship with diabetes
mellitus, which have led to a conclusion that there are
two types of lichen planus, i.e. the immunogenic type
and the metabolic defect type, both being associated
with diabetes mellitus (66,67).
Yellow nails
The lesion involves distal hallux and is quite common
in diabetic individuals (68). It is one of the important
markers of diabetes mellitus. The earliest sign is yellow
or brown color of the distal part of the hallux nail plate.
Later, a canary-yellowish discoloration occurs on the
nails. It can involve finger nails and other toe nails
during the later stage of the disease.
Eruptive xanthomas
They commonly occur in hyperlipidemic status.
Frequently, the underlying problem is uncontrolled
diabetes. The eruptions are multiple, firm, yellowish in
color, waxy papules ranging from 1 to 4 mm in diameter,
appearing in crops. They are mostly located on the
extensor surfaces. The firm nontender papules are
present on the knees, elbows, back, buttocks and trunk
(69). These lesions are itchy, sometimes tender,
surrounded by erythematous halo. They show
Koebners phenomena (70). The unifying factor in
hyperlipidemic status is decreased lipoprotein lipase
activity or increased LDL, making chylomicrons less
able to compete LDL for lipoprotein lipase. The net
result is an increase in plasma chylomicrons (71).
There is some evidence that eruptive xanthomas in
diabetics result from macrophages incorporating
plasma lipoprotein forming foam and xanthoma cells
(71). With correction of hyperlipidemia and
hyperglycemia, the lesions involute, sometimes with
postinflammatory hyperpigmentation and occasionally
scars.
Bullous pemphigoid
There are very few studies relating bullous
pemphigoid and diabetes. The relationship between
the two awaits for confirmation. Theoretically, their
association may be due to the lower threshold of
diabetes in traumatically induced blisters or on the
basis of antigenic changes at the level of lamina lucida
because of enzymatic glycosylation. Steroids and
sometimes even immunosuppressive drugs may be
appropriate.
Dermatitis herpetiformis
The HLA association of diabetes and dermatitis
herpetiformis may be a possible explanation for the two
diseases appearing together more frequently than
expected (72).
Psoriasis. It is a multifactorial disease of unknown
origin. There is a distinct pattern of associated diseases
existing in patients with psoriasis. Systemic disorders
such as hypertension and diabetes are often seen in
these patients. The reasons for these diseases to occur
in psoriasis patients have been related to nutritional
factors of hypercaloric dietary habits (73).
156
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