Diabetes mellitus and the skin

Abstract

Several dermatoses are routinely associated with diabetes mellitus, especially in patients with chronic disease. This relationship can be easily proven in some skin disorders, but it is not so clear in others. Dermatoses such necrobiosis lipoidica, granuloma annulare, acanthosis nigricans and others are discussed in this text, with an emphasis on proven link with the diabetes or not, disease identification and treatment strategy used to control those dermatoses and diabetes.

Keywords: Dermatology; Diabetes mellitus; Skin manifestations

Full text

Continuing mediCAl eduCAtion
Diabetes mellitus and the skin*
AdrianaLuciaMendes1 HelioAmanteMiot2
VidalHaddadJunior2
DOI: http://dx.doi.org/10.1590/abd1806-4841.20175514
Abstract:Severaldermatosesareroutinelyassociatedwithdiabetesmellitus,especiallyinpatientswithchronicdisease.This
relationshipcanbeeasilyproveninsomeskindisorders,butitisnotsoclearinothers.Dermatosessuchnecrobiosislipoidi-
ca,granulomaannulare,acanthosisnigricansandothersarediscussedinthistext,withanemphasisonprovenlinkwiththe
diabetesornot,diseaseidenticationandtreatmentstrategyusedtocontrolthosedermatosesanddiabetes.
Keywords: Dermatology; Diabetes mellitus; Skin manifestations
s
8
Received on 17.12.2015.
ApprovedbytheAdvisoryBoardandacceptedforpublicationon29.06.2016.
* Study conducted at the Departments of Dermatology and Clinical Medicine of the Faculdade de Medicina de Botucatu - Universidade Estadual Paulista “Júlio
deMesquitaFilho”(UNESP)–Botucatu(SP),Brazil.
Financial support: none.
 Conictofinterest:none.
1 DepartmentofClinicalMedicine-FaculdadedeMedicinadeBotucatu-UniversidadeEstadualPaulista“JúliodeMesquitaFilho”(UNESP)–Botucatu(SP),
Brazil.
2 DepartmentofDermatologyandRadiotherapy-FaculdadedeMedicinadeBotucatu-UniversidadeEstadualPaulista“JúliodeMesquitaFilho”(UNESP)–
Botucatu(SP),Brazil.
 ©2017byAnaisBrasileirosdeDermatologia
An Bras Dermatol. 2017;92(1):8-20.
INTRODUCTION
Diabetes mellitus (DM) is considered a modern epidemic
diseasethataffectsabout8.3%ofadults,whichaccountsfor382mil-
lionpeopleoftheglobalpopulation,and46%ofcasesareestimated
to be currently undiagnosed.1
Theincreasingurbanizationwithdietarychanges,reduced
physicalactivity,andchangesinotherlifestylepatterns,inaddition
to the increasing rates of obesity contributes to the greater preva-
lence of DM.
Besidesthe severe renal, vascularandophthalmiccompli-
cations,theskin maybe compromisedbyvariousdiseasesdirectly
related to diabetes or with associations not yet fully proven. The
mainonesarediscussed in this text,withanemphasisonproven
linkwithdiabetesornot,diseaseidenticationandtreatmentstrat-
egy used to control these dermatoses and diabetes.
ACANTHOSIS NIGRICANS
Acanthosisnigricans(AN) ischaracterizedbyskinthicken-
ing with hyperchromic and a velvety aspect that occurs mainly in
thefolds,especiallyinthearmpits(Figure1).Currently,itispostu-
latedthatis causedby hyperinsulinemia,whichpromotesthesyn-
thesisoftype1insulingrowthfactor(IGF1)thatleadstoepidermal
FIgure 1:
Armpitsarea
classic location
of acanthosis
nigricans. Note
the thickening
and hyperchro-
mia of the skin
Photo: De-
partment of
Dermatology,
Botucatu
MedicalSchool,
UNESP

An Bras Dermatol. 2017;92(1):8-20.
Diabetes mellitus and the skin 9
FIgure 2:
Bullosis diabet-
icorum blisters
are asymptom-
atic and exhibit
mildinamma-
tion
Photo: De-
partment of
Dermatology,
Botucatu
MedicalSchool,
UNESP
acanthosis.2Furthermore,AN can be associated to skin tags (ach-
rocordons)andacralpapilosis,whichcanhelpinscreeninginsulin
resistance among general population.
The disease may also be associated with certain malignan-
cies such as gastric cancer and high doses of niacinamide, but in
mostcases the patienthasalsotypeAinsulin resistance,although
adrenal and thyroid disease may be associated.3-5
Inobesepatients,AN seems to evolve in association with
the metabolic syndrome. The most affected sites are the armpits,
neck,areolas,umbilicusandelbows.Topicaltreatmentusingemol-
lients with basis of urea and oral metformin can be used (due to
insulinresistance), buttheonlyeffective measuresareweight loss
andphysicalexercises,which reverses the metabolic disturbances
that causes cutaneous manifestations.
BULLOSIS DIABETICORUM
Bullosis diabeticorum (BD),bullousdisease of diabetes or
diabetic blisters occurs in approximately 0.5% of diabetic patients.6
Itwasrstdescribedin1930,butonlyin1967thetermbullosisdia-
beticorum was proposed.7,8Eventhoughuncommon,itcanbecon-
sidered a distinct marker of DM and it is manifested in patients with
long history of evolution of diabetes or those who have complica-
tionssuchasnephropathyorneuropathy,althoughtherearereports
of concomitant appearance to the initial presentation of DM.8
BD has been reported in patients aged 17 to 80 years with
alarger proportion in males (2:1). The preferred locations are the
extremities,especiallylegsandfeet(Figure2).9
Pathophysiology of the BD bullae is still unknown. The
blisters are large, tense and characterized by suddenand sponta-
neous onset in acral regions.9,10 The diameter of the blisters varies
between0.5and5cm,theyareoftenbilateral,withaninammatory
base,and containaclear,sterile,nonserouscontent.10 Other affect-
ed places are the back and side of the hands and the arms.10 These
blisters are usually painless and non-pruritic and disappear sponta-
neously without scarring in 2 to 5 weeks.10,11
Outbreaks may occur, but risk factors are radiation and
trauma, blood glucose changes, magnesium and calcium alter-
ations,vasculardiseaseormicroangiopathyandkidneyfailure.9,11-15
Diagnosis is made on clinical basis and should be remem-
beredwhentherearelargeblisterswithoutapparentinammation
in longstanding diabetic patients or those with chronic complica-
tions of the disease.
Histologically, the blisters are manifested in three different
types based on the level of cleavage. The most common type shows
an subepidermal cleavage at the level of the lamina lucida without
acantholysis, which appear and disappear spontaneously, without
scarring.8,14 Blisters present hyaline content and are located at the
tipsofthetoesandlessfrequentlyinthedorsalsurfacesofthefeet.
Patients with these clinical manifestations have good circulation in
the affected limb and tend to present diabetic peripheral neuropathy.
The second type is rarer and involves lesions that may be
hemorrhagic including resolution with scars and atrophy.16 The
cleavageplaneisbelowthedermoepidermaljunction,withdestruc-
tionofanchoringbrils.17,18Athirddescribedtypeconsistsofmul-
tiple blisters associated with sun exposure and markedly tanned
skin.It affectsfeet, legs andarmsand mustbedistinguished from
porphyria cutanea tarda. 18
The differential diagnosis includes pemphigus, bullous
pemphigoid,contactdermatitis,insectbites,epidermolysisbullosa,
blisters by trauma, burns, bullous erysipelas, bullous drug erup-
tions and porphyria cutanea tarda.8,9,19
DIABETIC DERMOPATHY
Diabetic dermopathy (DD) is the most common specic
skin lesion in patients with diabetes. 20,21Thediseasewasrstde-
scribedbyHansMelinintheearly60s, ascircumscribedbrownish
lesions located in the lower limbs of diabetic patients and named as
diabeticdermopathybyBinkley(1965),whoconsidereditacutane-
ous manifestation of diabetic microangiopathy. 22,23
Its incidence may range from 7% to 70% of diabetic pa-
tients.5,20,2225DDisseenmoreofteninolderpatients,agedmorethan
50years,andinthosewithalonghistoryof diabetes.18,20Also,itis
morecommoninmen(2:1).20,22,26,27 There is some controversy as to
DD be a pathognomonic sign for diabetes since there are studies
thathaveshownitsinvolvementinnon-diabeticsubjects.6,27
The origin of DD is unknown and there is no relation with
decreased local perfusion.28Anotherpossibleexplanationisdueto
mild traumas that do not compromise wound healing.29,30 There
is also degeneration of subcutaneous nerves in patients with neu-
ropathy.31However,themostacceptableexplanationistherelation
between DD and microvascular complications of diabetes. Studies
haveshownstrongassociationwithDD,nephropathy,retinopathy
or neuropathy.20,30
Shemer et al.20 observed increased incidence of DD in 52-
81% when associated with such complications. Another study
showed that 42.9% of patients presented neuropathy associated
withDD(p<0.01)6 although about 21% of patients with DD showed
no evidence of microangiopathy. 20
The association between DD and cardiovascular disease has
alsobeenidentiedbasedonECGchanges,historyofcoronaryar-

10 Mendes AL, Miot HA, Haddad Jr V
An Bras Dermatol. 2017;92(1):8-20.
terydiseaseorboth.About53%ofpatientswithtype2diabetesand
DD had coronary artery disease.6DDassociation withneuropathy,
nephropathy,retinopathyandcoronaryarterydiseasemayindicate
a severity marker of the evolution of diabetes.31
AsDDtendstooccuroverbonyprominences,itissuggest-
ed that occur in response to sudden trauma.11,14,20,31 The association
betweentraumaandDDlesionsisfurtherconfusedbythefrequent
presence of peripheral neuropathy.31 Nevertheless, some studies
have failed to induce DD in vivo.32
DD consists of small, well-dened surface, brownish de-
pressions,with atrophicappearance,resemblingscars. Commonly
the lesions measure less than 1cm in diameter and present round-
edshape (Figure3). They canoccasionallyextend andreachup to
2.5cm. Depressions are smooth and hyperpigmented and intensity
of the pigment is related to the degree of atrophy. Generally asymp-
tomatic,itdoesnotcausepainoritchingandistypicallylocatedbi-
laterally in pretibial regions and distributed asymmetrically.21 More
rarely,DDoccursonthethighs,trunkandlowerabdomen.6,21,22 The
location and atrophic appearance causes many patients to consider
DD as scars resulting from a possible trauma.21,22 The appearance of
DDatthebeginningishardlydocumented,beinganunderreported
disease.
The progression of DD is variable and does not appear to
be affected by glycemic control.5,24,25Individual lesions may persist
onaveragefor18-24months and may stay indenitely.When the
diseaseregresses,the process is slow can be solved completely or
maintain pigmentation without atrophy. Cyclically, older lesions
disappear and new ones continuously evolve.21,22,23,32
The diagnostic is clinically based: after careful history and
physicalexamination,diagnosisofDDbecomesevident.Thepres-
ence of multiple, hyperpigmented, sharply demarcated atrophic
scars in the lower leg of a patient with diabetes is highly sugges-
tive of DD. The presence of four or more typical lesions in diabetic
patients is also characteristic of DD.10 Biopsy is not routinely per-
formed,sincethehistologyisnotspecicanditisinterestingavoid
trauma to the lower extremities in these individuals. However,
atypical features or unusual locations may hinder the diagnosis and
recommend the histopathological examination.31,32
Histologicndingsincludeatrophyofthedermalpapillae,
variablepigment at basal cells, thickening of the supercial blood
vesselsintima,hypertrophyandhyalinizationofthedeepestarteri-
oles,extravasatederythrocytes,hemosiderindepositionandamild
lymphocyticinltration.19,21,24Thereistelangiectasia,edema,and-
broblast proliferation at the papillary dermis.
The differential diagnosis of DD includes many diseases.
Early lesions of DD can be mistaken with fungal infection.23,While
typical brownish atrophic scars may require differentiation of
Schamberg’sdisease (progressivepigmented purpuric dermatitis),
purpura annularis telangiectasica, purpuric lichenoid dermatitis,
pigmentedstasisdermatitis,scarringlesions,papulonecrotictuber-
culids,factitious dermatitisandabrasions.23 Many of these entities
canbe differentiated by distribution, appearance and natural his-
tory.
Treatment of DD is not recommended and is little effective.30
Lesions are asymptomatic and can persist indenitely or make
spontaneous regression without treatment.21Nevertheless,thecon-
ditions associated with DD require attention. Patients should be
evaluatedforthediagnosisofDM,whichwhen is not conrmed,
shouldrequirefurtherinvestigations.Onceconrmedthepresence
of diabetes, attention should be focused on prevention, detection
andcontrolof associated complications. As with all patients with
diabetes,glycemiccontroliscritical.
SCLERODERMIFORM DISORDERS
Patients with diabetes may have thickening and hardening
oftheskinofthedorsalregionofthengeraswellastheskinover-
lyingthe jointsofthe hand andngers.The sclerosiscaneven ex-
tend these places. These changes are more common in type 1 diabe-
tes and occur in up to 50% of the patients. The cause seems to be the
glicosylation of proteins that appears to cause hardening of the skin.
Anotherform of skin sclerosisis associated with diabetes
isthe scleredema adultorum of Buschke (SAB), where sclerosis is
diffuse,butlocatedpreferablyontheback,havinganerythematous
appearance,and which maycompromisethe neck,shoulders,and
even other regions. It is more common in men over 40 years with
insulin dependent or multiple complications.
SABisararebromucinousconnectivetissuediseaseofun-
known etiology resistant to therapy and without spontaneous reso-
lution.33-35Itischaracterizedbysymmetricalanddiffusethickening
withhardeningoftheskinaffectingmainlytheface,trunk,neckand
upperlimbs, sparingthehands andfeet(Figure 4).36,37 The disease
presents no race, gender or age group preferences,however, it is
more common in middle-aged men. DM is associated with about
50% of cases.38 Its prevalence varies between 2.5 and 14% in diabetic
patients,butit isnoteworthy thatmostofthecasesareunderdiag-
nosed. 35,39,40
SAB has an insidious, asymptomatic, onset with progres-
sive loss of skin natural marks. In severe cases it can lead to neck
and back pain.41 Mobility is reduced and may lead to a restrictive
respiratory syndrome due to the skin thickening.42 The affected area
is painless and can present decreased sensitivity to touch.41Viscer-
FIgure 3: Diabetic dermopathy consists of small brownish-colored
depressionsin the skin surface, of atrophic appearance, which look
like scars
Photo: Department of Dermatology, Botucatu Medical School,
UNESP

Diabetes mellitus and the skin 11
An Bras Dermatol. 2017;92(1):8-20.
alinvolvementis rare,affectingeyes,tongue,pharynx, esophagus,
musculoskeletal tissue, joints, heart (pericardial and pleural effu-
sion)andhepatosplenomegaly.40,42,43
SABbelongsto thegroupofcutaneousmucinosesandcan
beassociatedwithbacterial,viral,hematologicaldisorders,diabe-
tes and other endocrine disorders.37,44 Three scleredema variants are
classically described.45
Type1-Occursmostofteninmiddle-agedwomen,children
andyoungpeople,presentsacuteonsetandisassociatedwithafe-
brilerespiratory illness, mostcommonlystreptococcalor viral (in-
uenza,chickenpox,measles,cytomegalovirusandHIV).46,47 This
variant has self resolution after several months or years.
Type 2 - There is no relation with infections, it is slow-
ly progressive and is associated with monoclonal gammopathy.48
This type tends to persist for years and may be at increased risk
formultiplemyeloma,beingassociatedwithotherdiseasessuchas
amyloidosis,rheumatoidarthritis, Sjögren’ssyndrome,obstructive
sleepapnea,primaryhyperparathyroidism,pituitaryadenomaand
adrenocortical disease. 40,44,49,50
Type3-associatedtodiabetes,whichcanbeeitheroftype
1 and type 2.33,51-54 It occurs generally in obese patients with long
standing diabetes and poor metabolic control, microangiopathy
and need for insulin.35,38,40 It affects middle-aged men with history
of longtime DM. This type also tends to persist and there is no clear
relation to prognosis or glycemic control.55
ThediagnosisofSABisclinical,butdiagnosticimaging(e.g.
ultrasonographyandmagneticresonance)canhelpinassessingthe
extent or disease activity.56,57 Due to the lack of skin elasticity and the
skinthickeningin scleredema, incisional biopsy is usually recom-
mendedtoconrmthediagnosis.36
Histopathology shows marked thickening of the reticular
dermis (2 to 3 times) with caliber collagen bundles separated by
bands of hyaline deposit mucin or hyaluronic acid best evidenced
at toluidine blue staining. The glycosaminoglycan deposit histologi-
cally corresponds to an hyperintensity on magnetic resonance.58
Clinically, the differential diagnosis must be established
withscleroderma,eosinophilicfasciitisandscleromyxedema.59
InSAB,the main mechanism of accumulationofextracel-
lular matrix components appears to be represented by an abnormal
geneexpression of extracellular protein(collagentype1,bronec-
tin,andtype3)ontheskininsteadofdecreasingclearingprocesses.
ThisderegulatedgeneisobservedinSABregardlessofthepresence
ofdiabetes.Themediatorsofbroblastactivationarestillunknown.
40Althoughdisappointingresponsetotreatment,varioustherapeu-
tic modalities are used: immunosuppressants (e.g. cyclosporine and
methotrexate), pentoxifylline, prostaglandin E1, intravenous im-
munoglobulin, penicillamine, antibiotics, systemic corticosteroids,
andintralesional,factorXIII,aminobenzoate,colchicineandDMSO
gel,radiotherapy,photochemotherapywith psoralenandultravio-
letA(PUVA),andrecently,tamoxifenandirradiationwithelectron
beam.36,41,42,50,59,60The therapymaybeeffective,probablydue to the
upregulationofcollagenasesynthesisbybroblastsandsubsequent
degradationofcollagenbers.33,60,61
Ingeneral,the disease has a good prognosis, and in most
cases is self-limited; however, there are severe cases with rapid
progression,anditishardtodetermine thebesttreatmentforcon-
trollingthediseaseandanalyzingthecostbenetratio.
It is noteworthy that its chronicity can cause alterations in
movement of the shoulders and impaired respiratory function.40
GRANULOMA ANNULARE
Granulomaannulare(GA) is arare,benign andself-limit-
ed dermatitis of the pre tibial regions and the extensor surfaces of
the limbs. The cutaneous lesions are similar to necrobiosis lipoidica
diabeticorum,but without causing atrophy of the epidermis.62,63 It
ischaracterized by papules thatoftenassumean annular congu-
ration.63
Its etiology is unknown, but appears to be involved with
responsetoinfectionssuchasHIV,hepatitisC,toxicagents,thyroid
diseases and malignancy.64,65GAassociationwithdiabetesiscontro-
versial and has been extensively studied. Samlaska et al.(1992), in
acasecontrolstudy, revealed no statisticallysignicantcorrelation
betweenGAandtype2DM,whileinaretrospectivestudy12% of
patientswithGAhad diabetes. Otherstudies have associated GA
with DM also in about 12% of the patients.66 68
GAaffects twice as many women thanmenand the most
commonlyaffectedareasarethoseexposedtotrauma,suchasbacks
ofthehandsandfeet,ngers,elbow,armsandlegs; sometimes the
scalpmaybeaffected(Figures5and 6).63When GAisgeneralized,
the trunk is affected in almost all cases. 64Inmostcasestheplaques
areasymptomatic,butmay presentmildand occasionalitchingor
a burning sensation.69
The lesions begin as rm, skincolored dermal papules,
whichexpandgraduallyinacentrifugalway.Theformatisannular,
witha central hyperpigmentation, and sometimes the papules are
franklyerythematous,becomingerythematous-brownishposterior-
ly.70 The papules of annular shape grow slowly and can measure
from 0.5 to 5.0cm.63
GAaffects mainly children and young people withoutdi-
FIgure 4: Buschke’sscleredemaischaracterizedbysymmetricaland
diffusethickening, with hardening of the skin mainly on the face,
cervical region and upper limbs
Photo: Department of Dermatology, Botucatu Medical School,
UNESP

12 Mendes AL, Miot HA, Haddad Jr V
An Bras Dermatol. 2017;92(1):8-20.
abetes but, in adults with diabetes, a disseminated form can occur,
which is expressed in about 0.5% to 10% of these patients. 63,64,66 The
generalized perforating form is characterized by umbilicated pap-
ules of about 4mm located at the extremities and it is most common-
ly seen in children and young adults.
The probable pathophysiology is a stimulus that triggers
the release of lymphokines by previously activated lymphocytes.
These lymphokines stimulate the synthesis and activity of collage-
nase, producing an inammatory reaction that modulates the for-
mation of granulomas.63
The duration of the disease is highly variable. Many le-
sions disappear spontaneously, without scarring, but it can last for
months to years. Disappeared lesions have about 40% chance to re-
appear.63 The lack of symptoms, scaling or blistering associated to
GA helps to differentiate it from other skin diseases such as tinea
corporis, pityriasis rosea, psoriasis, or annular erythema. Rarely, a
biopsy is needed to conrm the diagnosis. 66
Histologically, GA appears as a focal degeneration of collagen
in the upper and middle layers of the dermis, accumulation of histio-
cytes and multinucleated giant cells arranged in fence/ palisade.14
Although histology is very similar to that observed in necrobiosis
lipoidica, prominent mucin deposits in GA helps to differentiate it.
GA has a poor therapeutic response. Treatment usually is not
necessary because most of its injuries remit spontaneously within two
years.69 If the lesions become an unpleasant problem, the available
options include high-dose topical steroids, intralesional injection of
corticosteroids, PUVA, cryotherapy, or drugs such as niacinamide, in-
iximab, dapsone and topical calcineurin inhibitors. 69,70 Oral isotreti-
noin can be effective in symptomatic patients and the improvement of
lesions occurs in 90% of those with decreased itching and erythema,
even in resistant lesions associated with few adverse events compared
with other drugs. 11 Moreover, this treatment provides good aesthetic
response with a considerable improvement in patient quality of life.
NECROBIOSIS LIPOIDICA DIABETICORUM
Necrobiosis lipoidica (NL) is an idiopathic dermatosis of
unknown origin, occurring mainly in patients with diabetes. While
most diabetics do not develop this disease, its incidence ranges from
0.3% to 1.6% of these patients per year.71
Two thirds of diabetics with NL are insulin dependent.72
NL is not exclusive to diabetics because up to a third of cases occur
in non-diabetic subjects.73,74 Over the years, however, about 90% of
these will develop some degree of glucose intolerance or at least
will present a positive family history for diabetes.75,76,77 These facts
suggest that as soon as the diagnosis of the dermatosis is conrmed,
the research for diabetes should be initiated.
NL predominates in women (80% of cases), white, and it
manifests at any age, but prevails between the fourth and sixth de-
cades.75 A retrospective study from the Mayo Clinic showed that the
conrmed diagnosis of diabetes, abnormal plasma glucose or a fam-
ily history of diabetes occurred in 90% of patients.75
The glycated hemoglobin levels were not associated with
the appearance of lesions, indicating that hyperglycemia is not nec-
essary for the development of NL. Among yuastdua diabetes, type
1 patients have the earliest manifestations of NL.76
Multiple lesions are common, and are usually observed in
both legs (Figures 7 and 8).77 Approximately 35% of the lesions prog-
ress to ulceration.78 Patients occasionally present itching or burning
sensations in areas where they were asymptomatic and pain arises
after ulceration. Some patients report partial or complete anesthesia
at affected sites, due to probable local neural dysfunction.79 More than
half of diabetic patients with NL have neuropathy or microangiopa-
Figure 5:
Granuloma
annulare man-
ifests by ery-
thematous and
rm dermal
papules that ex-
pand gradually,
with central
hyperpigmen-
tation
Photo: Depart-
ment of Derma-
tology, Botucatu
Medical School,
UNESP
Figure 6: Detail of the granuloma annulare, showing inltration at
the edges of the lesion
Photo: Department of Dermatology, Botucatu Medical School,
UNESP

Diabetes mellitus and the skin 13
An Bras Dermatol. 2017;92(1):8-20.
thy. Spontaneous resolution is observed in 10% to 20% of cases.
Histopathologyshowsdisorganization and degeneration of
collageninbasementmembranethickeningandinammationofthe
underlying subcutaneous fat. NL pathophysiology is still unclear. The
primary cause of collagen degeneration appears to be an immune-
mediated vasculitis (autoimmune vasculitis). The presence of anti-
bodiesandC3atthedermoepidermaljunctionandaroundtheblood
vesselvasculitislesionssupportthis,butotherhistologicalfeaturesof
leukocytoclastic vasculitis were not observed. 80 Other studies suggest
thatNLisprimarilyacollagendiseasewithsecondaryinammation,
81-83and the presence of brin lesionsassociated with histiocytes in
palisades suggests delayed hypersensitivity reaction.84
Typical lesions of NL start in the pretibial areas with non scaly
erythematous papules that gradually enlarge and coalesce into large
plaques.85The plaques resultfromthe conuence of yellowishpap-
ules and often develop atrophic center that corresponds to the dermal
andepidermalatrophyassociatedwithsupercialtelangiectasias.86
Gradual expansion and variable erythema occur at the edg-
es,whichareoftenelevated.Itsshapeiselliptical,withserpiginous
margins.Theadjacentskinisreddishviolet,whilethecenteris yel-
low,indicating accumulation of lipids.77,78,87 The size of the lesion
may range from a few millimeters to several centimeters. When the
lesions become chronic, the sclerosis is well marked with porcel-
aneous aspect. The metabolic control appears to have no proven ef-
fectinthecourseofthedisease,althoughthereisareportthattight
glucose control reduces the incidence of NL.88,89
Thelesionsmayoccasionallyappearinotherareas,suchas
thethighs,poplitealregionandfeet.Othersitesareinvolvedin15%
ofcases and include abdomen, upperlimbs(especiallyhandsand
forearms)andscalp,where NLcan causeatrophyandalopecia.In
theface, thediseasemay harmtheeyelids andnose.In rarecases,
lesions were observed in the heel and penis.89 NL also can develop
inposttraumascars, old lesionsofsclerodermaand atthescarsof
BCG vaccine.79Whenlesionsariseonotherpartsofthebody,gener-
ally the lower limbs are affected too.
Diagnosis is made by clinical examination. Histopathologi-
calexaminationmayberequiredinearlylesionsorinpatientswith-
outadiagnosisofdiabetes.Sarcoidosis,granulomaannulare,lichen
sclerosus et atrophicus and stasis dermatitis may be differential di-
agnosis of NL. Ulcerated lesions can resemble pyoderma gangreno-
sum,tertiarysyphilisandcutaneousmycobacteriosis.
Patients should be advised to avoid potentially traumatic sit-
uations,suchascontactsports.Theyshouldtheadvisedtowearsocks
up to the knee or foam pads for protection.79In general, drugtreat-
ment has little effect and should be reserved for symptomatic relief.
Drugsusedwithvariableefcacyareintralesionalinjectionandoral
useofcorticosteroidsortopicalthreadsunderocclusion,clofazimine,
acetylsalicylicacid,dipyridamole,pentoxyphilineandchloroquine.
When the lesions are at, use of emollients is indicated.
Rhodes(1980) reported success with brinolytic therapy (derived
fromnicotinicacidandinositolnicotinate)in24of30cases; redness
and warmth are important adverse events.75
Morerecently,anti-TNFtherapieshavebeenused,although
therearenostudiesthat demonstrate decisivetherapeuticefcacy
yet.90 Strict glycemic control remains controversial in improving NL.
When the plaques become ulcerated, the treatment must involve
the prevention of secondary infection with systemic antibiotics and
dressings. 82,91,92
DIABETIC FOOT
Thediabeticfootis acomplexanddisablingentity,caused
byvarious factors, and it should betreatedby various specialties
such as general surgery, vascular surgery, orthopedics, endocri-
nologyanddermatology.Itburdenspatients’qualityoflife,public
health system and social security.
Classically,theso-calleddiabeticfootisachroniculcerthat
evolves after trauma or over a callus caused by changes in points
withalteredsensitivityduetodiabetesneuropathy(6070%)(Figure
9).Amuchsmallerproportionislinkedtoperipheralvascularisch-
emia(about15%).
The causes can coexist and about 25% of diabetics may pres-
ent foot ulcers during the development of the disease. 4,93
FIgure 7: Typical lesions of necrobiosis lipoidica begin in the pretib-
ial regions with non-squamous papules that gradually grow and
groupintolargeplaques
Photo: Department of Dermatology, Botucatu Medical School,
UNESP
FIgure 8: Detailoflesionsofnecrobiosislipoidica,showingcentral
atrophy
Photo: Department of Dermatology, Botucatu Medical School,
UNESP

Ulcersaredifcultto healduetotheunderlyingimmuno-
suppressionof the disease, hyperkeratotic borders and sometimes
ischemia.IntheUS,thediabeticfootisresponsiblefor70%oflower
limb amputations annually. 4,94
The treatment is performed according to the etiology. If the
pulsesarepalpable,energetictherapeuticmeasuressuchasthede-
bridement and dressing usually heal the wound in few weeks. On
theotherhand,nomeasuresareeffectiveinthepresenceofischemia
and surgical revascularization is crucial to the treatmentin these
cases. Secondary infections and osteomyelitis are factors that com-
plicate the approach and systemic antibiotics should be evaluated
in all cases.
There are specic guidelines to manage diabetic foot in a
multidisciplinary approach that surpass the scope of this text. 95
MISCELLANEOUS
Anichthyosiformaspectmayarisefromchangesoftheskin
in diabetes; it appear frequently in young subjects with insulin-
dependent diabetes and appear associated with microangiopathy
and duration of disease. Keratosis pilaris can also be observed and
both appear to be associated with skin xerosis seen in these patients.
Rubeosis is a vascular erythema on the face and neck pres-
entinupto60%ofpatientswithdiabetes,probablylinkedtothe
loss of the vasoconstrictor tone. It usually reects poor glycemic
controlandisassociatedtoperipheralneuropathy.Inthesepatients,
hyperglycemia can lead to a change in the microcirculation. It be-
comes clinically evident by facial venous dilatation. Rubeosis means
microangiopathy, anditis prudent toassesspatientsfor othermi-
croangiopathy such as retinopathy and nephropathy. Tight glucose
control is the mainstay of treatment for this disease.
Yellowskinorcarotenodermiaisalsorelatedtoinadequate
glycemic control, which occurs either by carotenemia, as well as
by increasing the glycosylation of collagen and dermal proteins.20
There is no treatment for this phenomenon.
FIgure 9: Diabetic foot may present a chronic ulcer on callus caused
by changes in sensitivity associated with diabetic neuropathy and
occasional ischemia
Photo: Department of Dermatology, Botucatu Medical School,
UNESP
Other conditions not necessarily related to the presence of
diabetes are the eruptive xanthomas.94 These lesions are observed
when there is a marked exacerbation of triglyceride levels (greater
than700mg/dL)causedbysometriggeringfactor,amongthemone
of the most common causes is the lack of DM control. The character-
isticlesionsmayappearaspapulesindiscreteorconuentdomes,
with waxy yellow centers and an erythematous base. Lesions may
developrapidlyoverthebuttocks,elbows,andknees.Theycan be
itchy and even painful. Eruptive xanthomas should be faced as a
lifethreatingdisorderleadingtoacutepancreatitisthatcanbequick-
ly resolved with proper correction of hypertriglyceridemia.83
Diabetes causes several changes in immunologic system,
but especially the decrease in leukocyte chemotaxis and phagocy-
tosis,inaddition,impairmentinvascularreactionleadstoasigni-
cantdeciencyofimmuneresponsethatfavorsinfectionsanddelay
their resolution.96
The most common fungal infections is candidiasis, espe-
ciallyvulvovaginal,balanopreputial,andangularstomatitis.These
may be the rst demonstration of the indirect presence of diabe-
tes. Vulvovaginalcandidiasis is almost universal among diabetic
women in the long term and is a common cause of vulvar itching
during periods of glycosuria. It comes with vulvar erythema and
sometimes with white discharge. Treatment involves glycemic con-
trolin additiontotopical or systemictreatmentfor specic fungal
infection.81
Othercommonsupercial mycoses in diabetics are exten-
sive pityriasis versicolor and dermatophytoses (e.g. tinea corporis),
which are associated to microangiopathy and poor glycemic con-
trol. Several opportunistic fungi infections are described in diabetics
withpoorglycemiccontrol.Averyseriouscondition,howeverrare,
ismucormycosis,causedbyZygomycetes,fromtheorderof Muco-
rales, which causes necrotic processes usually in the center of the
facewitharapidprogression,andwithahighmortalityrate.Early
identicationisessentialforsurvival.97
Bacterial infections may be varied and severe as those
caused by Staphylococcus or Pseudomonas. The infection may be mild
orsevereandmaymanifestasboils,abscessesorcarbuncles.Recur-
renterysipelasmayalsooccur,asnecrotizing/bullouserysipelasare
common among diabetics. External otitis by Pseudomonas is also a
seriousconditionindiabeticsandmayleadtomastoiditis,osteomy-
elitisofthetemporalbone,damagetonervesandmeninges,witha
high mortality rate.77 Infections in diabetics have to be considered
carefullyand requirehospitalizationdue to the sever compromise
of immune response.
As autoimmune disorders are associated among them-
selves,diabetes (especiallytype1 DM)canbe associatedtolupus
erythematosus,alopeciaareataandhalonevus.
VLTILIGO
Vitiligoisachronicdiseaseofautoimmuneetiologythatcan
manifest itself or,in most cases, associated with type 1 DM. It is
characterizedbyanabsenceordysfunctionofmelanocytesandap-
pears as hypo/ achromic spots surrounded by healthy skin whose
sizerangesfromafewmillimeterstolargeextensions,oftenlocated
aroundholes,extensorregions,chestandabdomen.98
14 Mendes AL, Miot HA, Haddad Jr V
An Bras Dermatol. 2017;92(1):8-20.

With an autosomal inheritance, it is estimated that vitili-
go is manifested among 1% to 7% of all diabetic patients and only
0.2% to 1% of the general population.74Althoughitspathogenesisis
notentirelyunderstood,itis suggested thatitscause is polygenic,
multifactorial,oracombinationofautoimmune,geneticandneuro-
humoral factors due to the impairment of nerve cells release toxic
substancesharmfultomelanocytes,leadingtodestructionofthese
cells while the pigment is forming.99Environmentalfactors,suchas
infectionor damage to the skin (Koebner phenomenon), may also
contribute to the appearance of lesions.99
Moretti et al.95 found that the epidermis of vitiligo has a sig-
nicantamount of cytokines in comparison with the healthy sur-
roundingskin,suggestingthattheproductionofthesecytokinesare
involved in apoptosis of melanocytes process and depigmentation
of the skin.96,99
Vitiligo can coexist with other disorders of autoimmune
etiology, especially hormonal disorders (thyroiditis, adrenal insuf-
ciency and hipoparatathyreoidism) as part of the polyglandular
autoimmune syndrome whose clinical manifestations may appear
infourdifferentways.Thetype1isthemostcommon(1:20,000in-
dividuals)andprogresseswithadrenalinsufciency,thyroiditisand
type1DM,aswellasatrophicgastritis,perniciousanemia,alopecia
areata,celiacdisease,myastheniagravisandhypogonadism.97,98So,
whendiagnosing vitiligo, physicians should be alert to the emer-
genceofotherautoimmunediseases,particularlytype1DM.100-102
Althoughvitiligoisasymptomatic,theunpleasantdiscom-
fort and psychological stress can be considerable.11 Cosmetic treat-
mentisanoptiontoimprovethequalityoflife.103Skincamouage
andmicropigmentationcanbeconsidered,asthetreatmentofvitil-
igo is unsatisfactory in general. Patients should be advised to avoid
sun exposure and use broad spectrum sunscreens. In small and lo-
calizedlesionstopicalcorticosteroidsaretherstchoicetreatment,
whileforwidespreadvitiligo,treatmentwithnarrowbandultravio-
let light B is more effective. 81
PSORIASIS
Psoriasisisachronicrecurrentimmunemediatedinamma-
torydisease,withstronggeneticcomponentthataffects23%ofthe
Caucasian population.104It can occuratanyage, although in most
cases it develops before 40 years of age and is rare in children.105
Its emergence or worsening can often be triggered by emo-
tionalfactors.Somestudieshavelinkedpsoriasiswithpoorerqual-
ityoflife, reducedlife expectancy,bad employment and nancial
problems for the patient and family.106,107
Theextent ofskininvolvement is variable,rangingfrom a
fewlocatedplaquestowidespreadinvolvement.Whentheinvolve-
mentismoderatetosevere(>10%oftheirbodysurfacearea)itis
often associated with psoriatic arthritis and metabolic syndrome,
which is a set of risk factors for cardiovascular disease whose uni-
fyingfactorisinsulinresistance,conferringapro-inammatoryand
prothrombotic state.108-110
Several studies have evidenced the association of psoria-
sis with cardiovascular diseases and components of the metabolic
syndrome (hypertension, obesity, dysglycemia or type 2 diabetes,
dyslipidemia, fatty liver disease) and chronic kidney disease.107,110
Psoriasis patients often are overweight or obese in greater propor-
tion.111-11 4 Furthermore, it was also observed highermortalitythan
the general population.115
Severaltheorieswerehypothesizedtoassociatetheconcur-
renceofthecomponentsofmetabolicsyndrome,prematureathero-
sclerosisandpsoriasis.Oneofthesesuggeststhatcommoninam-
matorypathwaysareinvolved in the pathophysiology of both, as
thecytokineproleandthe inammatory cell inltrate of T cells,
macrophages and monocytes are observed in both conditions.114-116
Thediagnosis ofpsoriasisis usuallyclinical,based onhis-
toryand physical examination, but may be conrmed by the his-
topathological examination, which will reveal very characteristic
aspects of the disease.107
Treatment of psoriasis depends on the clinical manifesta-
tionspresented,varyingfromthesimpleapplicationoftopicalmed-
ications in mild cases to more complex treatments for more severe
cases. The response to treatment also varies greatly from one patient
to another and the emotional component should not be overlooked.
Ahealthylifestyle,avoidingstress,willcontribute totheimprove-
ment. Moderate sun exposure is of great help as keeping the skin
well hydrated.
Although some drugs can negatively affect metabolic ho-
meostasis by increasing cardiovascular risk, nonpharmacological
interventions,such as nutrition education, smoking cessationand
practice of physical activity associated with weight loss, can im-
prove the response to treatments for psoriasis as well as reduce car-
diovascular risk.
Evenwithoutcompleteremissionofthedisease,properdis-
ease control promotes social rehabilitation of patients, improving
theability towork,and probablydecreasingtheriskof comorbid-
ities.107
FINAL CONSIDERATIONS
Severalcutaneousdiseasesarecausedormaybeinuenced
bysystemicdisordersandthis knowledge is of major importance
for the general practitioner.
DMisahighlyprevalentsystemicmetabolicdisease,whose
cutaneous manifestations can help in the early diagnosis of the dis-
ease,thusreectingglycemiccontrol,systemicimpairmentorover-
all prognosis of the disease.
Adequateglycemiccontrolandprimarypreventionofspe-
cicdamagetointernalorgansshouldbepromotedandreinforced
by dermatologists, although many dermatological manifestations
associated with DM are not necessarily related to glycemic levels
nordenitelyassociatedtothedisease.q
ACKNOWLEDGEMENTS: to the students Josiane Monção
Andrella(MedicalSchoolofBotucatu–UNESP)andMichelRaineri
Haddad(MedicalSchoolofSãoJosédoRio Preto–FAMERP)for
their help at various stages of the preparation of the manuscript.
Diabetes mellitus and the skin 15
An Bras Dermatol. 2017;92(1):8-20.

16 Mendes AL, Miot HA, Haddad Jr V
An Bras Dermatol. 2017;92(1):8-20.
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18 Mendes AL, Miot HA, Haddad Jr V
An Bras Dermatol. 2017;92(1):8-20.
How to cite this article: MendesAL,MiotHA,HaddadJuniorV.Diabetesmellitusandtheskin.AnBrasDermatol.
2017;92(1):8-20.
Mailing address:
Vidal Haddad Junior
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Caixa Postal 557
18618 970 Botucatu, SP.
Tel: 14 3880 1259
Email: haddadjr@fmb.unesp.br
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mortality in patients with psoriasis: results from a populationbased study. Arch
Dermatol. 2007;143:1493-9.
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systemic inflammatory diseases: potential mechanistic links between skin disease
and comorbid conditions. J Invest Dermatol. 2010;130:1785-96.
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of how severe psoriasis may drive cardiovascular comorbidity. Exp Dermatol.
2011;20:303-7.
116. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat
Immunol. 2011;12:204-12.

Diabetes mellitus and the skin 19
An Bras Dermatol. 2017;92(1):8-20.
Questions
s
1. Diabetes mellitus is considered a modern epidemic. The dis-
ease affects about:
a) 1.2% of adults
b) 8.3% of adults
c) 34.2% of adults
d) 9.4% of adults
2. Acanthosis nigricans is not associated with:
a) certain malignancies such as gastric cancer
b) high doses of niacinamide
c) typeAinsulinresistance
d) nodular melanoma
3. Regarding bullosis diabeticorum, select the wrong answer:
a) diabetic blisters occurs in approximately 0.5% of diabetic pa-
tients
b) the preferredlocalizationaretheback and side of the hands
and the arms
c) the diagnosis is made on clinical basis
d) the blisters are usually painless and non pruritic
4. Diabetic dermopathy is (select the wrong answer):
a) themostcommonspecicskinlesioninpatientswithdiabetes
b) associated with cardiovascular disease
c) a pathognomonic sign for diabetes
d) typically located bilaterally in pretibial regions and distributed
asymmetrically
5. The differential diagnosis of diabetic dermopathy includes (se-
lect the wrong answer):
a) Schamberg’sdisease(progressivepigmentedpurpuricderma-
titis)
b) stasispigmenteddermatitis,scarringlesions
c) factitious dermatitis
d) atopic dermatitis
6. Buschke´s scleredema (select the wrong answer):
a) is characterized by symmetrical and diffuse thickening with
hardening of the skin
b) affectsmainlytheface,trunk,neckandupperlimbs
c) is common in middle-aged men
d) is associated with diabetes mellitus in about 90% of cases.
7. Granuloma annulare is a benign and self-limited dermatitis
that (select the wrong answer):
a)is characterized by papules which often assume an annular
conguration
b) affects twice as many men than women
c) the generalized perforating form is characterized by umbili-
cated papules of about 4mm most commonly seen in children
and young adults
d) disappeared lesions have about 40% chance to reappear
8.Necrobiosislipoidicadiabeticorum(selectthewronganswer):
a) is not exclusive to diabetics because up to a third of cases occur
in nondiabetic patients
b) approximately 35% of the lesions progress to ulceration
c) typical lesions start up in the pretibial areas
d)conrmeddiagnosisofdiabetes,abnormalplasmaglucoseora
family history of diabetes occur in 40% of patients
9. The diabetic foot is a severe complication that (select the wrong
answer):
a) should be treated only by the dermatologist
b) is a chronic ulcer that evolves after trauma or over a callus
caused by changes in points with altered sensitivity caused by
diabetes neuropathy
c) In the US, is responsible for 70% of lower limb amputations
annually
d) if the pulses are palpable, energetic therapeutic measures as
the debridement and dressing usually heal the wound in a few
weeks
10. Rubeosis is a vascular erythema on the face and neck that (se-
lect the wrong answer):
a) is observed in up to 60% of patients with diabetes
b) reectspoorglycemiccontrol
c) becomes clinically evident by facial venous dilatation
d) the tight glucose control is not important for the treatment of
the disease
11. The eruptive xanthomas (select the wrong answer):
a) are observed when there is a marked exacerbation of triglycer-
idelevels(greaterthan700mg/dL)
b) appearaspapules in discreteor conuent domes,withwaxy
yellow centers and an erythematous base
c) thelesionsmaydeveloprapidlyoverthebuttocks,elbows,and
knees
d) do not resolve with proper correction of hypertriglyceridemia.
12. The most common fungal infections in diabetes mellitus (se-
lect the wrong answer):
a) is candidiasis, especially vulvovaginal, balanopreputial, and
angular stomatitis
b) vulvovaginal candidiasis is almost universal among diabetic
women in the long term and is a common cause of vulvar itch-
ing during periods of glycosuria
c)treatmentdoesnotneedglycemiccontrol,onlytopicalorsys-
temic treatment for Candida sp.
d)other common supercial mycoses indiabetics are extensive
pityriasis versicolor and dermatophytoses

20 Mendes AL, Miot HA, Haddad Jr V
An Bras Dermatol. 2017;92(1):8-20.
13. Which disease is not associated with diabetes mellitus?
a) lupus erythematosus
b) alopecia areata
c) acne conglobata
d) lichen planus
14.Vitiligo can coexist with other disorders of autoimmune etiol-
ogy, especially:
a) thyroiditis
b) type 2 diabetes
c) hipoparatathyreoidism
d) alopecia areata
15. Patients with diabetes may have thickening and hardening of
the skin (select the wrong answer):
a) of the dorsal region of the toes as well as the epidermis overly-
ingthejointsofthefootandtoes
b) these changes are more common in type 1 patients
c) occur in up to 50% of the patients
d) the cause seems to be the glicosylation of proteins
16. The etiology of the granuloma annulare is unknown, but ap-
pears that is not involved with:
a) infectionssuchasHIV
b) thyroid diseases
c) psoriasis
d) malignancy
17. Which body site is not compromised by the necrobiosis
lipoidica diabeticorum?
a) foot
b) oral mucosa
c) abdomen
d) penis
18. Bacterial infections in diabetes may be varied and severe.
Mark the wrong option:
a) are mainly caused by Staphylococcus or Pseudomonas
b) recurrent erysipelas may also occur, as necrotizing/bullous
erysipelas are commoner among diabetics.
c) External otitis by Pseudomonas is a mild condition in diabetics
d) the bacterial infections in diabetics have to be considered care-
fullyandrequirehospitalizationduetothesevercompromise
of immune response
19. Which drug is not used in the treatment of the necrobiosis li-
poidica diabeticorum?
a) intralesionalinjectionandoraluseofcorticosteroidsortopical
threads under occlusion
b) clofazimine
c) tamoxifen
d) acetylsalicylic acid
20. Select the correct answer:
a) Diabetes mellitus is a high prevalent systemic metabolic disor-
der whose cutaneous manifestations can help in early diagno-
sis,asreecteither theglycemiccontrol,organiccompromise
or overall disease prognosis.
b) Proper glycemic control and primary prevention of organ-
specicdamageshouldbereinforcedbydermatologists
c) many dermatologic manifestations during diabetes are not re-
latedtoglycemiclevelsnordenitelyassociatedtothedisease
d) all the statements are correct
Answer key
Palmar hyperhidrosis: clinical, pathophysiological, diagnostic
andtherapeuticaspects..2016;91(6):716-25.
1- C
2- B
3- D
4- D
5- A
6- D
7- B
8- C
9- D
10- C
11- B
12- A
13- B
14- C
15- C
16- C
17- B
18- D
19- B
20- B
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