Insulin Resistance and Skin Diseases · in adolescence and in female gender and is commonly...

See discussions stats and author profiles for this publication at httpswwwresearchgatenetpublication276176629

Insulin Resistance and Skin Diseases

Article middot May 2015

DOI 1011552015479354

CITATIONS

52READS

652

3 authors including

Maddalena Napolitano

Universitagrave degli Studi del Molise

115 PUBLICATIONS 855 CITATIONS

SEE PROFILE

Matteo Megna

University of Naples Federico II

134 PUBLICATIONS 913 CITATIONS

SEE PROFILE

All content following this page was uploaded by Matteo Megna on 13 May 2015

The user has requested enhancement of the downloaded file

Review ArticleInsulin Resistance and Skin Diseases

Maddalena Napolitano Matteo Megna and Giuseppe Monfrecola

Section of Dermatology Department of Medicina Clinica e Chirurgia University Federico II Napoli Italy

Correspondence should be addressed to Maddalena Napolitano maddynapolitanogmailcom

Received 18 February 2015 Accepted 17 March 2015

Academic Editor Uwe Wollina

Copyright copy 2015 Maddalena Napolitano et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

In medical practice almost every clinician may encounter patients with skin disease However it is not always easy for physiciansof all specialties to face the daily task of determining the nature and clinical implication of dermatologic manifestations Are theyconfined to the skin representing a pure dermatologic event Or are they alsomarkers of internal conditions relating to the patientrsquosoverall health In this review we will discuss the principal cutaneous conditions which have been linked to metabolic alterationsParticularly since insulin has an important role in homeostasis and physiology of the skinwewill focus on the relationships betweeninsulin resistance (IR) and skin diseases analyzing strongly IR-associated conditions such as acanthosis nigricans acne andpsoriasis without neglecting emerging and potential scenarios as the ones represented by hidradenitis suppurativa androgeneticalopecia and hirsutism

1 Introduction

The skin is the major border organ of human body beingthe most exposed to environmental variations However italso offers a window to what is going on inside the bodyso that changes to the skin may signal a more serioushealth problem frequently serving as amarker for underlyinginternal disease [1 2] Numerous internal diseases are ableto present cutaneous manifestations which may precedeoccur concurrently with or follow the onset of the internalconditions There are a huge number of studies regardingthe relationship of the most common skin manifestations ofinternal diseases (eg diabetes inflammatory bowel diseaseslupus erythematosus systemic sclerosis and tumors) [1 2]However the surveys regarding the relationship betweenmetabolic alterations such as insulin resistance (IR) anddermatologic conditions are still scant

In this review we will discuss the principal skin diseasesand dermatological conditions which have been linked toIR analyzing the mechanisms of the connections betweencutaneous and metabolic deregulations (Table 1)

2 Insulin Insulin Resistance and Skin

Insulin a polypeptide hormone produced by the beta cellsof the islets of Langerhans of the pancreas controls the level

of the glucose in the blood so is a central player in themetabolic system Insulin binding to the insulin receptorleads to receptor autophosphorylation and recruitment ofadaptormolecules such as insulin receptor substrates (IRS 1ndash6)or Shc which are in turn phosphorylated and serve as bindingsites to initiate the activation of different signaling cascadesincluding the mitogen-activated protein kinase (MAPK) andphosphoinositide 3-kinase (PI3-K) pathways [3]These path-ways not only regulate glucose lipid and proteinmetabolismbut also control mitogenic responses through the controlof proliferation differentiation and apoptosis (Figure 1)Insulin signaling is downregulated through inhibitory serinephosphorylation of IRS 1 thus rendering the cells resistantto insulin Interestingly inflammatory mediators such ascytokines can induce IR through the activation of IRS kinases[4] Furthermore insulin has an important role in homeosta-sis and physiology of the skin although the exact functionof insulin signaling remains controversial Under healthyconditions insulin regulates the equilibrium between pro-liferation and differentiation of keratinocytes a prerequisitefor the formation of the epidermal structure Under con-ditions of chronic inflammation (eg acne or psoriasis)high levels of proinflammatory cytokines activate p38MAPKwhich induces IR by serine phosphorylation of IRS leadingto blockade of differentiation and at the same time to

Hindawi Publishing Corporatione Scientific World JournalVolume 2015 Article ID 479354 11 pageshttpdxdoiorg1011552015479354

2 The Scientific World Journal

Insulin

IRS

PI3K

Akt

GSK-3mTORC 1

Ras

Mek

MAP kinase

General geneexpression

Cell growth

GLUT 4 translocation

GLUT 4

GLUT 4

Glucose

S6K1

IGF 1

AR activation FOXO-1

FOXO-1 is excluded from the nucleus and degraded in the cytoplasm in a

ubiquitin-dependent mannerFOXO-1AR

P

PP

P P PP

P

vesicle

differentiation

Figure 1 Insulin signalling pathway insulin binds to the insulin receptor leading to its autophosphorylation and recruitment of adaptormolecules such as insulin receptor substrates (IRS 1ndash6) to engage multiple downstream signalling pathways IRS activation can be alsotriggered by IGF-1 signalling Phosphoinositide 3-kinase (PI3-K)Akt mammalian target of rapamycin (mTOR) and the Rasmitogen-activated protein kinase (MAPK) pathways represent themajor cellular signalling pathways activated Particularly AKT controls the assemblyof glucose transporter- (GLUT-) 4 at the cell membrane and thus controls glucose influx into the cell mTOR complex 1 (mTORC1) activatesthe kinase S6K1 which phosphorylates and inhibits IRS and thus reduces AKT-GLUT-dependent glucose uptake the principal mechanism ofperipheral insulin resistance AKT phosphorylation pathway inhibits FOXO-1 mediated gene expression by its extrusion from the nucleus tothe cytoplasm preventing FOXO-1 mediated repression of androgen receptors GSK-3 = glycogen synthase kinase 3 and FOXO-1 = forkheadbox protein O-1

an increased proliferation of basal keratinocytes [3] IR isdefined clinically as the inability of a known quantity ofexogenous or endogenous insulin to increase glucose uptakeand utilization in an individual as much as it does in a normalpopulation It causes an insufficiency in insulin-stimulatedglucose transport in the skeletal muscle and fat tissue as wellas a suppression of glucose production in the liver [5] Inaddition as a result of the IR the pancreas produces muchmore insulin than normal This condition called hyperin-sulinemia accelerates lipogenesis with increased productionof free fatty acids reduces levels of sex hormone bindingglobulin (SHBG) increases luteinizing hormone (LH) andfollicle stimulating hormone (FSH) levels and finally leadsto an increase in the production of ovarian androgens andalso in their biologically active portion potentially leadingto hyperandrogenism (Figure 2) [6 7] Hyperandrogenisma common endocrine disorder of women of reproductive age

with a prevalence of 5ndash10 comprises a heterogeneous groupof conditions that exhibit a common phenotype The mostfrequent hyperandrogenic-linked disorder is the polycysticovary syndrome (PCOS) It shows an 80ndash85 prevalenceamongwomenwith excess androgen and is also closely linkedto IR [8] The clinical signs of hyperandrogenism are veryimportant especially for the dermatologist since they includethe following hirsutism alopecia seborrhea acne and insevere cases signs of virilization (deepening of the voiceincreased muscle mass clitoromegaly decreased breast sizeand amenorrhea) highlighting the wide clinical scenariowhich is related to IR and hyperinsulinemia As regardsIR and hyperinsulinemia evaluation although the glucose-insulin relationship is clinically relevant it is also importantto recognize that theoretically IR responds to influencesother than glucose metabolism The reference standard forthe evaluation of insulin sensitivity is the glucose clamp test

The Scientific World Journal 3

Table 1 Skin diseases associated with insulin resistance

Skin disorders and insulin resistance (IR)

Conditions stronglyassociated with IR

Conditionspotentially associated

with IR

Conditionsanecdotally linked to

IRAcanthosis nigricans Acrochordons Alopecia areata

Acne Androgeneticalopecia Vitiligo

Psoriasis HidradenitissuppurativaHirsutism

Hyperandrogenism

However this test is limited to research use and is difficultto perform at all medical institutions [9] Homeostasis modelassessment (HOMA) first described in 1985 by Matthews etal is a method for estimating insulin sensitivity It is calcu-lated by multiplying fasting plasma insulin (FPI) by fastingplasma glucose (FPG) then dividing by the constant 225[10] Compared with the ldquogoldrdquo standard euglycemic clampmethod for quantifying IR quantification using HOMA ismore convenient This method has been applied across allethnic groups One study suggested that the range of normalHOMA-IR in a healthy Hispanic population may be higherthan the one in Caucasians in central and north Americaand certainly this population is known to have a geneticsusceptibility to type 2 diabetes which is closely associatedwith IR Indeed the best cutoff of HOMA-IR in Hispanicpopulation seems to be 380 for the definition of IR This ishigher than the widely adopted cutoff of 260 for Caucasianpopulation [11] Therefore in spite of its importance the lackof a standardized reference range forHOMA-IR has hinderedits clinical and population application However Katz et alproposed a new formula to calculate insulin sensitivity thatrelies less on insulin levels called the quantitative insulinsensitivity check index (QUICKI) [12] Some authors haveobserved that QUICKI has a better correlation with theeuglycemic clamp than HOMA-IR and a lower coefficient ofvariation Sarafidis et al and Antuna-Puente et al reporteda coefficient of variation for this index based on two fastingglucose and insulin samples of 78 and 39 respectively [1314] However even considering these advantages the formulais still rarely used in clinical studies compared to HOMA-IR

3 Material and Methods

We searched for English-language literature describing therelationships between insulin resistance and skin diseases inthe following commonly usedwebsites PubMed (httpwwwpubmedcom) Google (httpwwwgooglecom) Googlescholar (httpscholargooglecom) Scopus (httpwwwscopuscom) and EBSCO (httpwwwebscocom) Thefollowing keywords were used insulin insulin resistanceskin diseases obesity cutaneous diseases diabetes cutaneousmanifestations dermatologic conditions internal diseasesand cutaneous disorders

Genes

Diet Obesity Physical inactivity

Insulin resistance

Hyperinsulinemia Hyperandrogenemia

LH release

darr IGFBP-1 997888rarr uarr Free IGF-1

darr SHBG

Figure 2 Connections between insulin resistance hyperinsuline-mia and hyperandrogenism FSH = follicle stimulating hormoneIGF = insulin-like growth factor IGFBP = insulin-like growthfactor binding protein LH = luteinizing hormone and SHBG = sexhormone binding globulin

4 Skin Diseases Strongly Associated with IR

41 Acanthosis Nigricans Acanthosis nigricans a cutaneouscondition affecting localized areas of the skin is amongthe most common dermatologic manifestations of obesityand IRhyperinsulinemia Indeed hyperinsulinemia is ableto stimulate insulin-like growth factor (IGF) receptors withsubsequent keratinocyte proliferation [15] The activity ofIGF-1 is regulated by IGF binding proteins (IGFBPs) whichincrease IGF-1 half life deliver IGFs to target tissues andregulate the levels of the metabolically active ldquofreerdquo IGF-1IGFBP-1 and IGFBP-2 are both decreased in obese subjectswith hyperinsulinemia increasing plasma concentrations offree IGF-1 An increase in bioactive IGF-1 promotes cellgrowth and differentiation [16 17] IGF-1 is expressed withinthe stratum granulosum and by dermal fibroblasts but not byepidermal basal keratinocytes In theory an insulin-inducedsystemic reduction of IGFBP-1 and IGFBP-2 could increaselocal levels of free IGF-1 thereby facilitating the developmentof hyperkeratosis and papillomatosis observed in acanthosisnigricans [18] The prevalence of this condition varies from7 to 74 according to age race frequency of type degreeof obesity and concomitant endocrinopathy It is most com-mon in Native Americans followed by African AmericansHispanics and Caucasians [19] This condition appears assymmetric velvety hyperpigmented plaques that may occurin almost any location It is most commonly observed inthe axilla groin and posterior neck but can also be seen onthe elbows knuckles and face particularly in ethnic skinThe hyperpigmentation observed is secondary to acanthosis


and papillomatosis of the epidermis rather than pigment-producing cells [20] Many classifications of AN have beenproposed Curth classified AN into benign (obesity relatedhereditary and endocrine forms) and malignant (associatedwith tumour) forms [21] In 1994 Schwartz proposed aclassification including benign and malignant forms formsassociated with obesity and drugs acral acanthosis nigricansunilateral acanthosis nigricans and mixed and syndromicforms [22] Burke et al classified AN according to severityon a scale of 0ndash4 based on how many areas are affected Thisscale is easy to use having a high interobserver reliability thatcorrelates with fasting insulin and body mass index (BMI)[23] Many therapies have been attempted for AN includingtopical and oral treatments Topical retinoid (tazarotene)is considered first-line treatment it is epidermopoietic andcauses a reduction of the stratum corneum replacement time[19 24] Trichloroacetic acid (TCA) is a superficial chemicalexfoliating agent causing destruction of the epidermis withsubsequent repair and rejuvenation TCA (15) is causticand causes coagulation of skin proteins leading to frostingPrecipitation of proteins leads to necrosis and destructionof epidermis followed by inflammation and activation ofwound repair mechanisms This leads to reepithelializationwith replacement of smoother skin [25] Other topical treat-ments including calcipotriol surgical excision urea salicylicacid and triple-combination depigmenting cream (tretinoin005 hydroquinone 4 and fluocinolone acetonide 001)with sunscreens are other options [19]

Systemic therapies oral retinoids (isotretinoin acitretin)can be effective probably through regulation of proliferationand differentiation of keratinocytes Metformin and rosigli-tazone are useful in AN characterized by IR they reduceglucose production by increasing peripheral insulin respon-siveness reducing hyperinsulinemia body weight and fatmass and improving insulin sensitivity in peripheral musclesParticularly in this context metformin seems to function asa multipathway inhibitor of mechanistic target of rapamycincomplex 1 (mTORC1) kinase affecting the pathogenesis ofmTORC1-driven anabolic and hyperproliferative diseases ofWestern civilization (obesity diabetes etc) [26] A low-calorie diet increasing physical activity andweight reductioncan improve the IR state thus decreasing the severity of theskin disease [27]

42 Acne Acne is a chronic inflammation of the folliculop-ilosebaceous unit (FPSU) due to hyperkeratosis and asso-ciated with sebaceous hypersecretion It is more prevalentin adolescence and in female gender and is commonlylocated on face shoulders back and chest with lesions thatrange from noninflammatory open or closed comedones(blackheads and whiteheads) to inflammatory lesions whichmaybe papules pustules or nodules [28 29] Acne is themostcommon skin disease being often widely and improperlyconsidered to be a simple self-limited disorder of adolescents[30] However acne may also be a common componentof many systemic diseases or syndromes which are alsousually linked to IR [31] This is the case in seborrhea-acne-hirsutism-androgenetic alopecia (SAHA) syndrome poly-cystic ovarian syndrome (PCOS) and hyperandrogenism IR

and acanthosis nigricans (HAIR-AN) syndrome conditionswhich may all require metabolic and hormonal evaluationsaswell as insulin-sensitizingmedications [32] In this contextPCOS represents the most common and well known clinicalscenario which links IR and acne Indeed PCOS whichis typically characterized by hyperandrogenism chronicanovulation and polycystic ovaries shows acne in 70 ofcases with 19 to 37 of women with moderate to severeacne meeting the criteria for this disorder [33 34] Inparticular acne that originates or persists into adulthood andis refractory to conventional therapies should raise suspicionfor underlying PCOSWomenwith PCOS have abnormalitiesin the metabolism of androgens and estrogen and in thecontrol of androgen production moreover PCOS is alsoassociated with peripheral IR and hyperinsulinemia [35 36]Since insulinIGF-1 receptors are expressed in epidermal ker-atinocytes hyperinsulinemiamay lead to an increased prolif-eration of basal keratinocytes within the FPSU duct inducingfailure of terminal differentiation of follicular corneocytesthus actively participating in acne pathogenesis Further-more insulin also stimulates the synthesis of androgensleading to high sebum production a recognized correlate ofacne severity [9 37] Moreover IGF-1 is able to stimulate 5120572reductase adrenal and gonadal androgen synthesis androgenreceptor signal transduction sebocyte proliferation sebumproduction and lipogenesis affecting acne development [3839] Indeed IGF-1 is the growth promoter of puberty playinga central role in acne and the induction of hyperandrogenismas highlighted by the fact that IGF-1-overtreated Laronpatients usually exhibit hyperandrogenism [40] Apart fromPCOS the close relationship between acne and IR is alsohighlighted by recent studies which showed that hypergly-caemic carbohydrates and insulinotropicmilkdairy productsare linked to diabetes and may drive acne pathogenesispromoting increased insulinIGF-1 signaling and supportingalso a connection betweenmilk products acne and increasedbody mass index (BMI) [41ndash47] Since high BMI is a majorcomponent of the metabolic syndrome it is therefore notsurprising that acne patients may often exhibit increasedlevels of serum glucose and insulin as well as IR as recentlyreported by Del Prete et al and Demir et al [28 48] Inthis context Western diet and lifestyle two main actors ofWestern civilization appear to be the linking points betweenacne IR and metabolic syndrome [49] Indeed acne isabsent in populations consuming less insulinotropic palae-olithic diets that exclude grains milk and dairy productsand exhibit much lower insulinIGF-1 signalling [41 5051] Conversely the Western diet is characterized by highglycaemic load and increased high levels of milkdairy pro-tein containing abundant amounts of branched-chain aminoacids (leucine isoleucine and valine) These two dietarystimuli are able to overstimulate a kinase termedmammaliantarget of rapamycin complex 1 (mTORC1) The activation ofmTORC1 signalling is involved in both acne pathogenesis(altering sebaceous gland homeostasis with the promotionof cell growth and proliferation) and IR (stimulating thekinase S6K1 which negatively controls insulin signalling atthe level of insulin receptor substrate-1 phosphorylation)[44 49 52] Moreover milk and dairy products act as


enhancers of insulinIGF-1 signalling supporting sebaceouslipogenesis and acne aggravation through the derepres-sion of the androgen receptor [45 46 53ndash55] Indeed alipid-enriched sebaceous gland microenvironment may thenpromote excessive proliferation of Propionibacterium acnesand the lipophilic yeast Malassezia furfur with resultantinflammatory reactions of the pilosebaceous follicle [56]Studies are also accumulating suggesting that low glycemic-load diet is able to improve acne [42 57] Moreover there isevidence that a low glycaemic load diet can reduce the sizeof sebaceous glands decrease inflammation and diminishthe expression of proinflammatory interleukin-8 all showinga positive influence on the clinical course and intensityof acne and sebum production [42 58] Overall it hasbeen interesting to note that the complex nutrient-regulatedmTORC1 signalling pathway is the crucial molecular connec-tion between acne theWestern diet and IRThis is mediatedthrough phosphoinositide 3-kinase (PI3-K) AKT kinase thetranscription factor FoxO1 androgen receptors insulin andIGF-1 [44] A major role is played by FoxO1 It represses theandrogen receptor thus restricting access to that receptorFoxO1 is inactivated by its extrusion from the nucleus tothe cytoplasm induced by high glycaemic load dairy proteinconsumption and increased insulinIGF-1 signalling so thatit is not able to suppress hepatic IGF-1 synthesis inhibit themagnitude of androgen signalling interact with regulatoryproteins important for sebaceous lipogenesis and regulatethe activity of innate and adaptive immunity as well asto act as a rheostat of mTORC1 the master regulator ofcell growth proliferation and metabolic homoeostasis Allthis drives increased protein and lipid synthesis cell pro-liferation cell differentiation including hyperproliferation ofacroinfundibular keratinocytes sebaceous gland hyperplasiaincreased sebaceous lipogenesis IR and increased BMIhighlighting their parallel involvement in acne pathogenesis[59] Interestingly isotretinoin one of the major acne treat-ments is able to deeply influence mTORC1 pathway with itsmajor effects linked to modifications of PI3KAKTFoxO1signalling further confirming their important role in acnedevelopment [60]

In conclusion acne appears to develop in a metabolicenvironment with an increased activity of mTORC1 show-ing itself much more like a systemic rather than a skindisease Therefore dermatologists may not solely focus ontreating acnersquos skin pathology but should appreciate the greatopportunity to introduce dietary andmetabolic interventionsso as to prevent more serious mTORC1-driven diseases ofcivilization like obesity diabetes and cancer

43 Psoriasis Psoriasis is a chronic skin inflammatory dis-ease which is now considered a systemic immunomediateddisorder Patients suffering from psoriasis exhibit differentclinical phenotypes that represent its dynamic spectrum [61]The most common psoriasis type accounting for up to 90of cases is psoriasis vulgaris in which papulosquamousplaques are well delineated from surrounding normal skinThese plaques are salmon to pink lesions covered by whiteor silvery scales which are usually distributed symmetricallyon the extensor aspects of elbows and knees scalp andor

lumbosacral region [62] Psoriasis patients are at high riskto develop cardiovascular and metabolic diseases includingdiabetes as well as metabolic syndrome [63] conversely itis also well established that overweight and obesity are riskand exacerbating factors for psoriasis itself [64 65] Howeverthe strict clinical connection between psoriasis andmetabolicdiseases (obesity metabolic syndrome etc) is also under-lined by analogies in their pathogenesis (chronic inflamma-tion) showing factors like adipose tissue (AT) excess and IRas drive linking points Indeed AT is now recognized as apart of the innate immune system and adipocytokines activefactors secreted by AT have an important role in the patho-genesis of both IR and psoriasis [63 66 67] For exampleadipocytokines such as leptin and adiponectin which are ableto regulate and affect insulin sensitivity through modulationof insulin signaling and the molecules involved in glucoseand lipid metabolism are deregulated in a very similar wayin both psoriasis and obesity highlighting themechanisms ofthe possible common association with IR observed in thosepatients (eg plasma levels of adiponectin are decreased inobesity psoriasis IR and type 2 diabetes) [68ndash71] Moreoverthese adipokines have also been found to regulate a huge vari-ety of immune functions (cytokines production T cells differ-entiation etc) showing an active role in the pathophysiologyof psoriasis highlighting the close connection of immuno-logical and metabolic alterations and linking the bases ofpsoriasis and IR [68 72 73] Other adipocytokines apart fromleptin and adiponectinmay also be involved in the associationbetween IR and psoriasis This is the case with omentin aprotein produced by stromal vascular cells of visceral AT Itincreases insulin sensitivity by stimulating insulin-mediatedglucose uptake in human adipocytes Indeed serum levels ofomentin inversely correlated with fat mass were found to bedecreased in patients with psoriasis and negatively correlatedwith BMI and waist circumference [74] Moreover psoriasispatients also showed altered levels of further adipokinessuch as visfatin and resistin both of which have metabolicfunctions also playing an important role in insulin sensitivity[75ndash77] Another example of the tight relationship betweenpsoriasis and IR is displayed by TNF-120572 one of the majoractors of psoriasis pathogenesis as demonstrated by the effi-cacy of anti-TNF-120572 treatments in psoriasis TNF-120572 is also ableto induce insulin signaling defects by acting on adipocytesand muscle cells impair insulin signaling through inhibitionof the tyrosine kinase activity of the insulin receptor andsuppress the secretion from adipocytes of adiponectin ananti-inflammatory molecule that also functions in regulatinginsulin sensitivity [78 79] Furthermore protein wingless-typeMMTV integration site familymember 5a (wnt5a) levelswere shown to be upregulated in psoriatic skin lesions [80]Wnt5a was also reported to be significantly higher in leanpatients with psoriasis compared with lean healthy controlsand in obese patients compared with obese healthy controlssuggesting that in psoriasis an increase in wnt5a maycontribute to the development of metabolic comorbidity [81]Indeed wnt5a is released from adipose tissue macrophagesand was shown to be of importance in the developmentof IR [82] Therefore it is not surprising that literature isaccumulating that shows that patients with psoriasis (with or


without psoriatic arthritis) commonly share obesity relatedcomplications such as metabolic syndrome dyslipidemiadiabetes andor IR [67 83 84] Particularly Pereira et alrecently found a significant association between psoriasis andIRwith an odds ratio of 263 of abnormal glucose homeostasisin psoriatics compared to controls suggesting that treatmentsfor psoriasis must also be designed to encourage lifestylealterations such as diet modifications and exercise in addi-tion to pharmacotherapy [85] Moreover insulin sensitivityindices were reported to be significantly lower in psoriaticsas compared with controls with serum insulin level and IRindices demonstrating a significant positive correlation withthe severity of psoriasis and being decreased after systemictreatments [86 87] These findings were recently confirmedbyGyldenloslashve et al who showed that normal glucose-tolerantpatients with moderate to severe psoriasis had significantlyreduced insulin sensitivity compared with age- gender-and body mass index-matched healthy control subjectssupporting the notion that psoriasis per se may constitutea prediabetic condition [88] Furthermore the associationbetween IR and psoriasis has been also reinforced by anotherrecent study which showed that PCOS prevalence in apsoriatic cohortwas higher than in nonpsoriaticwomen (47versus 11) highlighting that women with PCOS and psori-asis had a greater probability of IR hyperinsulinaemia anddyslipidaemia as well as a more severe skin condition thanthose with psoriasis alone [89] IR has also been indicated asan important contributing mechanism to the development ofpsoriasis itself driving not only cardiovascular comorbiditiesbut also its cutaneous phenotype Particularly Buerger etal reported that IR directly contributed to the epidermalphenotype (hyperproliferation and altered differentiation ofkeratinocytes) seen in psoriasis suggesting that key cytokinesinducing IR in keratinocytes and kinases mediating theireffects may represent attractive targets for novel antipsoriatictherapies [3] Following this thinkingmedications developedfor diabetes had been studied in clinical trials for use inpsoriasis therapy [90 91] In particular thiazolidinedionesa novel class of insulin-sensitizing drugs have demonstratedpromise for treatment of psoriasis Thiazolidinediones acti-vate peroxisome proliferator-activated receptors (PPAR) atype of steroidthyroid ligand-activated nuclear receptor thatis expressed on human keratinocytes In culture ligands forperoxisome proliferator-activated receptor inhibit prolifera-tion of both normal and psoriatic human keratinocytes [91]andnewer thiazolidinediones pioglitazone and rosiglitazonehave been demonstrated effective for treatment of psoriasis[92 93] even if another recent study did not confirm theseresults [94]

However the use of these PPAR activators in patientsshowing dermatologic diseases has to be deeply evaluatedfor example these drugs increase sebum production whichis not a favorable condition for acne patients [95]

In conclusion psoriasis appears to be closely associatedwith IR Psoriatic patients are at high risk of developing IRwhich is itself able to influence keratinocytesrsquo homeostasisand psoriasis pathogenesis There are numerous molecularfactors responsible for this close connection with AT andadipokines play a key role in both conditions

5 Skin Diseases Potentially Associated with IR

51 Acrochorda Acrochorda or skin tags are pedunculatedsoft brown papules most commonly seen on the neck and inthe axillae and groin they are frequently seen in associationwith acanthosis nigricans Skin tags are harmless and do notusually cause pain but they are unsightly and are a sourceof discomfort A few studies have been reported regardingthe abnormalities of carbohydrate andor lipid metabolismsin patients with skin tags [96ndash98] Indeed Kahana et al didnot find an increased incidence with obesity but did reportthat those patients with acrochorda had greater impairmentof carbohydrate metabolism [99] Skin tags may be removedwith cauterization cryosurgery ligation or excision [100]

52 Androgenetic Alopecia Androgenetic alopecia (AGA)is a hereditary thinning of hair induced by androgens ingenetically susceptible individuals [101] It has a polygenicpattern the risk of AGA is known to be influenced by familyhistory and genetic factors but precisely which gene(s) areinvolved is not clear [102] In the presence of androgensanagen phase is shortened and hair follicles shrink or becomeminiaturized With successive anagen cycles the folliclesbecome smaller and short nonpigmented vellus hairs replacethick pigmented terminal hairsThe thinningmay be diffuseinvolving most of the scalp but being more marked in thefrontal and parietal regions In general the frontal hairlineis maintained with temporal recession in some womenRarely advanced thinning with the recession of frontalhairline occurs in virilization associated with markedly ele-vated circulating androgen levels [103] Disagreements existregarding the relationship between IR and AGA althoughinsulin was suggested to play a role in the regulation ofcutaneous androgen metabolism and hair-growth cycle In2009 Nabaie et al did not find an association between IRand AGA and suggested that IR may result from aging ratherthan AGA or due to the presence of metabolic syndrome[104] Later this was confirmed by other studies no trueassociation exists between AGA and IR but their coexistenceas in the case of metabolic syndrome could contribute toworsening of AGA [101] On the other hand Matilainen et alreported a strikingly increased risk of hyperinsulinaemia andIR-associated disorders such as obesity hypertension anddyslipidemia inmenwith early onset of androgenetic alopecia(lt35) compared with age-matched controls supporting thehypothesis that early alopecia could be a clinical markerof IR [105] Moreover very recently Bakry et al reporteda significantly higher mean value of fasting serum insulinin AGA cases than in controls Further 35 of cases and19 of controls had IR with significant difference betweenboth groups [106] confirming the results of previous studieswhich found a relationship between IR and early baldness[107ndash109] Thus a reduction in insulin sensitivity may playa pathogenetic role in the miniaturization of hair follicles inthe regulation of androgen metabolism and the hair growthcycle all of which are relevant to the loss of scalp hair inmale-pattern baldness and [104 109 110] whether IR inducesor promotes AGA needs to be clarified by further studiesHowever it is advised that cases with early onset AGA should


be assessed for components of metabolic syndrome and IRfor early detection and control of cardiovascular risk factors[106]

53 Hidradenitis Suppurativa Hidradenitis suppurativa(HS) also known as acne inversa is a chronic follicular occlu-sive skin disorder characterized by recurrent abscesses drain-ing sinuses and scarring tracts predominantly but not exclu-sively involving apocrine gland-bearing skin HS mainlyaffects the intertriginous body areas including the axillaethe inguinal folds the anogenital the perineum the infra-mammary regions and the nape [111] It is a common skindisease affecting 2ndash4 of the population [112]The etiologyof HS is still poorly understood However it appears to becaused primarily by increased outer root sheath keratinocyteproliferation in the follicular portion of the FPSU leadingto follicular duct occlusion This is followed by rupture ofthe sebofollicular canal and extrusion of contents includingcorneocytes bacteria yeast sebum and pilar residua rup-tured hair follicles into the surrounding dermis and thedevelopment of a polymorphous inflammatory infiltrate[113] Increased prevalence of the metabolic syndrome isknown in patients suffering from HS Therefore studiesattempting to demonstrate primary hyperandrogenism as acause of the disease have been complicated by the fact thatthe majority of these patients are obese While this associa-tion further suggests obesity is an exacerbating factor [114]it is important to note that the foods of the Western diet thattrigger the follicular occlusion and the IR are the same onesresponsible for the obesity The problem is not the obesity(thin patients also suffer from HS) it is the diet

54 Hirsutism Hirsutism affecting up to 15 of women ischaracterized by excessive growth of terminal hair in theandrogen-sensitive skin regions The presence of hirsutisminwomen can lead to significant psychological morbidity andcan negatively influence the quality of lifeThemost commoncause of hirsutism is PCOS highlighting the close link and theimportance in its pathogenesis played by IR [115] Howeveridiopathic hirsutism (IH) the second most common causeof hirsutism is defined as hirsutism associated with normalovulatory function and normal circulating serum androgenconcentrations [116] Unluhizarci et al found a higher preva-lence (187) of impaired glucose tolerance among womenwith IH suggesting its association with IR [117] These resultswere further confirmed by Abdel Fattah and Darwish whohighlighted the presence of IR in IH as in PCOS independentof a high BMI suggesting that despite not being the onlyresponsible factor IR can contribute to the aetiopathogenesisof IH [118]

6 Skin Diseases Anecdotally Linked to IR

61 Alopecia Areata Alopecia areata (AA) is a common formof nonscarring alopecia involving the scalp andor bodycharacterized by hair loss without any clinical inflammatorysigns In general population the prevalence was estimated at07ndash38 [119] Alopecia areata has been described as being

associated with diseases of the endocrine glands various ten-sion states and emotional shock errors of refraction vitiligoand neurodermatitis and as a result of reflex irritations fromfocal lesions such as dental abscesses and from traumaticinjuries [120] Karadag et al for the first time showed thatIR is significantly higher in AA than in controls Increasedinflammatory cytokines and hypothalamic-pituitary-adrenalaxis activation may be responsible for this finding [121]

62 Vitiligo Vitiligo also called white spot disease or leuko-derma is a disease in which the skin loses its pigment dueto the destruction of melanocytes Vitiligo affects 1-2 ofthe worldrsquos population [122] In 2011 one study evaluated therelationship between vitiligo and IR A total of 96 subjectswere included in the study 57 patients with vitiligo and 39subjects in an age- and a body mass index-matched controlgroup Comparison between the vitiligo and the controlgroups revealed that patients with vitiligo had higher IR (23versus 20119875 lt 001) higher insulin andC-peptide levels (119875 lt0001 119875 lt 0001 resp) higher LDLHDL ratio and lowerHDL-C levels (119875 lt 001 119875 lt 00001 resp) The associationbetween these two conditions is not yet clear [123]

7 Conclusions

Clinicians must always keep in mind that skin disorders maybe a clue to internal alterations andor diseases as is the caseof acanthosis nigricans alopecia hirsutism and so forthOn the other hand numerous studies have also shown thatsome cutaneous diseases may be manifestations of systemicrather than simply skin disorders Particularly it is now wellknown that psoriasis acne and hidradenitis suppurativa canbe frequently associated with metabolic anomalies andorcomorbidities In this review we have shown the principaldermatologic conditions linked to IR We wish to underlinethe necessity for the dermatologist to expand his attentionbeyond skin pathology so as to not miss the major opportu-nity for motivation of dietary and metabolic evaluations andinterventions in order to properly support patientsrsquo health

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Authorsrsquo Contribution

Maddalena Napolitano and Matteo Megna have equallycontributed to the paper

References

[1] A G Franks Jr ldquoSkin manifestations of internal diseaserdquoMedical Clinics of North America vol 93 no 6 pp 1265ndash12822009

[2] D Rigopoulos G Larios and A Katsambas ldquoSkin signs ofsystemic diseasesrdquoClinics in Dermatology vol 29 no 5 pp 531ndash540 2011

[3] C Buerger B Richter K Woth et al ldquoInterleukin-1Β inter-feres with epidermal homeostasis through induction of insulin


resistance implications for psoriasis pathogenesisrdquo Journal ofInvestigative Dermatology vol 132 no 9 pp 2206ndash2214 2012

[4] C M Taniguchi B Emanuelli and C R Kahn ldquoCritical nodesin signalling pathways insights into insulin actionrdquo NatureReviews Molecular Cell Biology vol 7 no 2 pp 85ndash96 2006

[5] A S Karadag D T Ertugrul S Gunes Bilgili Z Takci E TutalandH Yilmaz ldquoInsulin resistance is increased in alopecia areatapatientsrdquo Cutaneous and Ocular Toxicology vol 32 no 2 pp102ndash106 2013

[6] H H G de Moura D L M Costa E Bagatin C T Sodre andMManela-Azulay ldquoPolycystic ovary syndrome a dermatologicapproachrdquo Anais Brasileiros de Dermatologia vol 86 no 1 pp111ndash119 2011

[7] E Carmina F Rosato A Jannı M Rizzo and R A LongoldquoRelative prevalence of different androgen excess disorders in950women referred because of clinical hyperandrogenismrdquoTheJournal of Clinical EndocrinologyampMetabolism vol 91 no 1 pp2ndash6 2006

[8] D A Ehrmann ldquoPolycystic ovary syndromerdquoTheNew EnglandJournal of Medicine vol 352 no 12 pp 1223ndash1236 2005

[9] K Okita H Iwahashi J Kozawa et al ldquoHomeostasis modelassessment of insulin resistance for evaluating insulin sensitiv-ity in patientswith type 2 diabetes on insulin therapyrdquoEndocrineJournal vol 60 no 3 pp 283ndash290 2013

[10] D R Matthews J P Hosker A S Rudenski B A Naylor DF Treacher and R C Turner ldquoHomeostasis model assessmentinsulin resistance and beta-cell function from fasting plasmaglucose and insulin concentrations in manrdquo Diabetologia vol28 no 7 pp 412ndash419 1985

[11] TMWallace J C Levy and D RMatthews ldquoUse and abuse ofHOMA modelingrdquo Diabetes Care vol 27 no 6 pp 1487ndash14952004

[12] A Katz S S Nambi K Mather et al ldquoQuantitative insulinsensitivity check index a simple accurate method for assess-ing insulin sensitivity in humansrdquo The Journal of ClinicalEndocrinologyampMetabolism vol 85 no 7 pp 2402ndash2410 2000

[13] P A Sarafidis A N Lasaridis P M Nilsson et al ldquoValidityand reproducibility of HOMA-IR 1HOMA-IR QUICKI andMcAuleyrsquos indices in patients with hypertension and type IIdiabetesrdquo Journal ofHumanHypertension vol 21 no 9 pp 709ndash716 2007

[14] B Antuna-Puente M Faraj A D Karelis et al ldquoHOMA orQUICKI is it useful to test the reproducibility of formulasrdquoDiabetes amp Metabolism vol 34 no 3 pp 294ndash296 2008

[15] J A Hud Jr J B Cohen J M Wagner and P D Cruz JrldquoPrevalence and significance of acanthosis nigricans in an adultobese populationrdquo Archives of Dermatology vol 128 no 7 pp941ndash944 1992

[16] S Y Nam E J Lee K R Kim et al ldquoEffect of obesity ontotal and free insulin-like growth factor (IGF)-1 and theirrelationship to IGF-binding protein (BP)-1 IGFBP-2 IGFBP-3insulin and growth hormonerdquo International Journal of Obesityvol 21 no 5 pp 355ndash359 1997

[17] K Siddle B Ursoslash C A Niesler et al ldquoSpecificity in ligandbinding and intracellular signalling by insulin and insulin-likegrowth factor receptorsrdquo Biochemical Society Transactions vol29 no 4 pp 513ndash525 2001

[18] SM RudmanM P Philpott G AThomas andT Kealey ldquoTherole of IGF-I in human skin and its appendages morphogen aswell as mitogenrdquo Journal of Investigative Dermatology vol 109no 6 pp 770ndash777 1997

[19] M M Phiske ldquoAn approach to acanthosis nigricansrdquo IndianDermatology Online Journal vol 5 no 3 pp 239ndash249 2014

[20] G Yosipovitch A DeVore and A Dawn ldquoObesity and the skinskin physiology and skin manifestations of obesityrdquo Journal ofthe American Academy of Dermatology vol 56 no 6 pp 901ndash916 2007

[21] H O Curth ldquoClassification of acanthosis nigricansrdquo Interna-tional Journal of Dermatology vol 15 no 8 pp 592ndash593 1976

[22] R A Schwartz ldquoAcanthosis nigricansrdquo Journal of the AmericanAcademy of Dermatology vol 31 no 1 pp 1ndash19 1994

[23] J P Burke D E Hale H P Hazuda and M P Stern ldquoAquantitative scale of acanthosis nigricansrdquo Diabetes Care vol22 no 10 pp 1655ndash1659 1999

[24] S Kapoor ldquoDiagnosis and treatment of Acanthosis nigricansrdquoSkinmed vol 8 no 3 pp 161ndash165 2010

[25] A Zayed R M Sobhi and D M Abdel Halim ldquoUsingtrichloroacetic acid in the treatment of acanthosis nigricans apilot studyrdquo Journal of Dermatological Treatment vol 25 no 3pp 223ndash225 2014

[26] B C Melnik and G Schmitz ldquoMetformin an inhibitor ofmTORC1 signalingrdquo Journal of Endocrinology Diabetes amp Obe-sity vol 2 no 2 p 1029 2014

[27] T Hermanns-Le A Scheen and G E Pierard ldquoAcanthosisnigricans associated with insulin resistance pathophysiologyand managementrdquo American Journal of Clinical Dermatologyvol 5 no 3 pp 199ndash203 2004

[28] M Del PreteM CMauriello A Faggiano et al ldquoInsulin resist-ance and acne a new risk factor for menrdquo Endocrine vol 42no 3 pp 555ndash560 2012

[29] S Titus and J Hodge ldquoDiagnosis and treatment of acnerdquoAmeri-can Family Physician vol 86 no 8 pp 734ndash740 2012

[30] H P M Gollnick A Y Finlay and N Shear ldquoCan we defineacne as a chronic disease If so how and whenrdquoThe AmericanJournal of Clinical Dermatology vol 9 no 5 pp 279ndash284 2008

[31] W Chen B Obermayer-Pietsch J-B Hong et al ldquoAcne-asso-ciated syndromes models for better understanding of acnepathogenesisrdquo Journal of the European Academy of Dermatologyand Venereology vol 25 no 6 pp 637ndash646 2011

[32] C C Zouboulis ldquoAcne as a chronic systemic diseaserdquo Clinics inDermatology vol 32 no 3 pp 389ndash396 2014

[33] F Borgia S Cannavo F Guarneri S P Cannavo M Vac-caro and B Guarneri ldquoCorrelation between endocrinologicalparameters and acne severity in adult womenrdquo Acta Dermato-Venereologica vol 84 no 3 pp 201ndash204 2004

[34] P Timpatanapong and A Rojanasakul ldquoHormonalprofiles andprevalence of polycystic ovary syndrome in women with acnerdquoJournal of Dermatology vol 24 no 4 pp 223ndash229 1997

[35] R Azziz ldquoDiagnostic criteria for polycystic ovary syndrome areappraisalrdquo Fertility and Sterility vol 83 no 5 pp 1343ndash13462005

[36] E Housman and R V Reynolds ldquoPolycystic ovary syndromea review for dermatologists Part I Diagnosis and manifesta-tionsrdquo Journal of the American Academy of Dermatology vol 71no 5 pp 847e1ndash847e10 2014

[37] S R Edmondson S P Thumiger G A Werther and CJ Wraight ldquoEpidermal homeostasis the role of the growthhormone and insulin-like growth factor systemsrdquo EndocrineReviews vol 24 no 6 pp 737ndash764 2003

[38] M K Arora A Yadav and V Saini ldquoRole of hormones in acnevulgarisrdquo Clinical Biochemistry vol 44 no 13 pp 1035ndash10402011


[39] R Kumari and D Thappa ldquoRole of insulin resistance and dietin acnerdquo Indian Journal of Dermatology Venereology and Lepro-logy vol 79 no 3 pp 291ndash299 2013

[40] B Klinger S Anin A Silbergeld R Eshet and Z LaronldquoDevelopment of hyperandrogenism during treatment withinsulin-like growth factor-I (IGF-I) in female patients withLaron syndromerdquo Clinical Endocrinology vol 48 no 1 pp 81ndash87 1998

[41] L Cordain S LindebergM Hurtado K Hill S B Eaton and JBrand-Miller ldquoAcne vulgaris a disease of western civilizationrdquoArchives of Dermatology vol 138 no 12 pp 1584ndash1590 2002

[42] R N Smith N J Mann A Braue H Makelainen and G AVarigos ldquoThe effect of a high-protein low glycemic-load dietversus a conventional high glycemic-load diet on biochem-ical parameters associated with acne vulgaris a randomizedinvestigator-masked controlled trialrdquo Journal of the AmericanAcademy of Dermatology vol 57 no 2 pp 247ndash256 2007

[43] B C Melnik ldquoEvidence for acne-promoting effects of milk andother insulinotropic dairy productsrdquoNestle NutritionWorkshopSeries Pediatric Program vol 67 pp 131ndash145 2011

[44] B C Melnik ldquoDiet in acne further evidence for the role of nut-rient signalling in acne pathogenesisrdquo Acta Dermato-Venereo-logica vol 92 no 3 pp 228ndash231 2012

[45] C A AdebamowoD Spiegelman C S Berkey et al ldquoMilk con-sumption and acne in adolescent girlsrdquo Dermatology OnlineJournal vol 12 no 4 article 1 2006

[46] C A AdebamowoD Spiegelman C S Berkey et al ldquoMilk con-sumption and acne in teenaged boysrdquo Journal of the AmericanAcademy of Dermatology vol 58 no 5 pp 787ndash793 2008

[47] B Melnik ldquoThe pathogenic role of persistent milk signaling inmTORC1- and milk- microRNA-driven type 2 diabetes mel-litusrdquo Current Diabetes Reviews vol 11 no 1 pp 46ndash62 2015

[48] B Demir H Ucak D Cicek S Aydin I Erden and S BDertlioglu ldquoChanges in serum desnutrin levels in patients withacne vulgarisrdquo European Journal of Dermatology vol 24 no 5pp 589ndash593 2014

[49] B C Melnik S M John and G Plewig ldquoAcne risk indicatorfor increased body mass index and insulin resistancerdquo ActaDermato-Venereologica vol 93 no 6 pp 644ndash649 2013

[50] S Lindeberg M Eliasson B Lindahl and B Ahren ldquoLowserum insulin in traditional Pacific IslandersmdashtheKitava studyrdquoMetabolism vol 48 no 10 pp 1216ndash1219 1999

[51] B C Melnik S M John and G Schmitz ldquoOver-stimulation ofinsulinIGF-1 signaling by western diet may promote diseasesof civilization lessons learnt from laron syndromerdquo Nutritionamp Metabolism vol 8 article 41 2011

[52] B C Melnik ldquoDietary intervention in acne attenuation ofincreased mTORC1 signaling promoted by Western dietrdquoDermato-Endocrinology vol 4 no 1 pp 20ndash32 2012

[53] T Norat L Dossus S Rinaldi et al ldquoDiet serum insulin-like growth factor-I and IGF-binding protein-3 in Europeanwomenrdquo European Journal of Clinical Nutrition vol 61 no 1pp 91ndash98 2007

[54] F L Crowe T J Key N E Allen et al ldquoThe association betweendiet and serum concentrations of IGF-I IGFBP-1 IGFBP-2and IGFBP-3 in the European prospective investigation intocancer and nutritionrdquo Cancer Epidemiology Biomarkers andPrevention vol 18 no 5 pp 1333ndash1340 2009

[55] C A Adebamowo D Spiegelman F W Danby A L FrazierW C Willett and M D Holmes ldquoHigh school dietary dairyintake and teenage acnerdquo Journal of the American Academy ofDermatology vol 52 no 2 pp 207ndash214 2005

[56] J P Leeming K T Holland andW J Cuncliffe ldquoThemicrobialcolonization of inflamed acne vulgaris lesionsrdquo British Journalof Dermatology vol 118 no 2 pp 203ndash208 1988

[57] R N Smith N J Mann A Braue H Makelainen and G AVarigos ldquoA low-glycemic-load diet improves symptoms in acnevulgaris patients a randomized controlled trialrdquoThe AmericanJournal of Clinical Nutrition vol 86 no 1 pp 107ndash115 2007

[58] H H Kwon J Y Yoon J S Hong J Jung M S Park and D HSuh ldquoClinical and histological effect of a low glycaemic load dietin treatment of acne vulgaris in Korean patients a randomizedcontrolled trialrdquo Acta Dermato-Venereologica vol 92 no 3 pp241ndash246 2012

[59] B C Melnik and C C Zouboulis ldquoPotential role of FoxO1 andmTORC1 in the pathogenesis of Western diet-induced acnerdquoExperimental Dermatology vol 22 no 5 pp 311ndash315 2013

[60] B C Melnik ldquoThe role of transcription factor FoxO1 in thepathogenesis of acne vulgaris and the mode of isotretinoinactionrdquo Giornale Italiano di Dermatologia e Venereologia vol145 no 5 pp 559ndash571 2010

[61] A Balato L Di Costanzo C Patruno F Ayala M Megna andN Balato ldquoPsoriasis or lsquopsoriasesrsquordquoGiornale Italiano di Derma-tologia e Venereologia vol 148 no 6 pp 649ndash650 2013

[62] C E Griffiths and J N Barker ldquoPathogenesis and clinicalfeatures of psoriasisrdquoTheLancet vol 370 no 9583 pp 263ndash2712007

[63] B B Davidovici N Sattar P C Jorg et al ldquoPsoriasis andsystemic inflammatory diseases potential mechanistic linksbetween skin disease and co-morbid conditionsrdquo Journal ofInvestigative Dermatology vol 130 no 7 pp 1785ndash1796 2010

[64] L Naldi L Chatenoud D Linder et al ldquoCigarette smokingbody mass index and stressful life events as risk factors forpsoriasis results from an Italian case-control studyrdquo Journal ofInvestigative Dermatology vol 125 no 1 pp 61ndash67 2005

[65] L Barrea N Balato C Di Somma et al ldquoNutrition and pso-riasis is there any association between the severity of the dis-ease and adherence to the Mediterranean dietrdquo Journal ofTranslational Medicine vol 13 no 1 2015

[66] N Balato M Megna F Palmisano et al ldquoPsoriasis and sport anew allyrdquo Journal of the European Academy of Dermatology andVenereology vol 29 no 3 pp 515ndash520 2015

[67] E Toussirot F Aubin and G Dumoulin ldquoRelationshipsbetween adipose tissue and psoriasis with or without arthritisrdquoFrontiers in Immunology vol 5 article 368 2014

[68] A Yadav P Jyoti S K Jain and J Bhattacharjee ldquoCorrelationof adiponectin and leptin with insulin resistance a pilot studyin healthy North Indian populationrdquo Indian Journal of ClinicalBiochemistry vol 26 no 2 pp 193ndash196 2011

[69] A Yadav M A Kataria V Saini and A Yadav ldquoRole of leptinand adiponectin in insulin resistancerdquo Clinica Chimica Actavol 417 pp 80ndash84 2013

[70] R M Abdel Hay and L A Rashed ldquoAssociation between theleptin gene 2548GA polymorphism the plasma leptin andthe metabolic syndrome with psoriasisrdquo Experimental Derma-tology vol 20 no 9 pp 715ndash719 2011

[71] S Coimbra H Oliveira F Reis et al ldquoCirculating adipokinelevels in Portuguese patientswith psoriasis vulgaris according tobody mass index severity and therapyrdquo Journal of the EuropeanAcademy of Dermatology and Venereology vol 24 no 12 pp1386ndash1394 2010

[72] G Fantuzzi ldquoThree questions about leptin and immunityrdquoBrain Behavior and Immunity vol 23 no 4 pp 405ndash410 2009


[73] GMatarese SMoschos andC SMantzoros ldquoLeptin in immu-nologyrdquo The Journal of Immunology vol 174 no 6 pp 3137ndash3142 2005

[74] S A Ismail and S A Mohamed ldquoSerum levels of visfatin andomentin-1 in patients with psoriasis and their relation to diseaseseverityrdquoThe British Journal of Dermatology vol 167 no 2 pp436ndash439 2012

[75] A Johnston S Arnadottir J E Gudjonsson et al ldquoObesity inpsoriasis leptin and resistin as mediators of cutaneous inflam-mationrdquo British Journal of Dermatology vol 159 no 2 pp 342ndash350 2008

[76] D Koczan R Guthke H-J Thiesen et al ldquoGene expressionprofiling of peripheral blood mononuclear leukocytes frompsoriasis patients identifies new immune regulatorymoleculesrdquoEuropean Journal of Dermatology vol 15 no 4 pp 251ndash2572005

[77] E Toussirot D Binda CGueugnon andGDumoulin ldquoAdipo-nectin in autoimmune diseasesrdquo Current Medicinal Chemistryvol 19 no 32 pp 5474ndash5480 2012

[78] B Gustafson A Hammarstedt C X Andersson and U SmithldquoInflamed adipose tissue a culprit underlying the metabolicsyndrome and atherosclerosisrdquo Arteriosclerosis Thrombosisand Vascular Biology vol 27 no 11 pp 2276ndash2283 2007

[79] M Wakkee H B Thio E P Prens E J G Sijbrands and HA M Neumann ldquoUnfavorable cardiovascular risk profiles inuntreated and treated psoriasis patientsrdquo Atherosclerosis vol190 no 1 pp 1ndash9 2007

[80] J E Gudjonsson A Johnston S W Stoll et al ldquoEvidence foraltered wnt signaling in psoriatic skinrdquo Journal of InvestigativeDermatology vol 130 no 7 pp 1849ndash1859 2010

[81] S GerdesM Laudes K NeumannH Baurecht andUMrowi-etz ldquoWnt5amdasha potential factor linking psoriasis to metaboliccomplicationsrdquo Experimental Dermatology vol 23 no 6 pp439ndash440 2014

[82] D Y Oh and J M Olefsky ldquoWnt fans the flames in obesityrdquoScience vol 329 no 5990 pp 397ndash398 2010

[83] I Grozdev N Korman and N Tsankov ldquoPsoriasis as a systemicdiseaserdquoClinics inDermatology vol 32 no 3 pp 343ndash350 2014

[84] A W Armstrong C T Harskamp and E J Armstrong ldquoPso-riasis and metabolic syndrome a systematic review and meta-analysis of observational studiesrdquo Journal of the AmericanAcademy of Dermatology vol 68 no 4 pp 654ndash662 2013

[85] R Pereira S T Amladi and P K Varthakavi ldquoA study of theprevalence of diabetes insulin resistance lipid abnormalitiesand cardiovascular risk factors in patients with chronic plaquepsoriasisrdquo Indian Journal of Dermatology vol 56 no 5 pp 520ndash526 2011

[86] M Rajappa S Rathika M Munisamy L Chandrashekar andD M Thappa ldquoEffect of treatment with methotrexate and coaltar on adipokine levels and indices of insulin resistance andsensitivity in patients with psoriasis vulgarisrdquo Journal of theEuropean Academy of Dermatology and Venereology vol 29 no1 pp 69ndash76 2015

[87] S Boehncke D Thaci H Beschmann et al ldquoPsoriasis patientsshow signs of insulin resistancerdquoBritish Journal of Dermatologyvol 157 no 6 pp 1249ndash1251 2007

[88] M Gyldenloslashve H Storgaard J J Holst T Vilsboslashll F KKnop and L Skov ldquoPatients with psoriasis are insulin resistantrdquoJournal of American Academy of Dermatology vol 72 no 4 pp599ndash560 2015

[89] F Moro C de Simone A Morciano et al ldquoPsoriatic patientshave an increased risk of polycystic ovary syndrome results ofa cross-sectional analysisrdquo Fertility and Sterility vol 99 no 3pp 936ndash942 2013

[90] J Varani N Bhagavathula C N Ellis and H A PershadsinghldquoThiazolidinediones potential as therapeutics for psoriasis andperhaps other hyperproliferative skin diseaserdquo Expert Opinionon Investigational Drugs vol 15 no 11 pp 1453ndash1468 2006

[91] C N Ellis J Varani G J Fisher et al ldquoTroglitazone improvespsoriasis and normalizes models of proliferative skin diseaseligands for peroxisome proliferator-activated receptor-120574 inhibitkeratinocyte proliferationrdquo Archives of Dermatology vol 136no 5 pp 609ndash616 2000

[92] N Shafiq S Malhotra P Pandhi M Gupta B Kumar and KSandhu ldquoPilot trial pioglitazone versus placebo in patients withplaque psoriasis (the P6)rdquo International Journal of Dermatologyvol 44 no 4 pp 328ndash333 2005

[93] A Malhotra N Shafiq S Rajagopalan S Dogra and S Mal-hotra ldquoThiazolidinediones for plaque psoriasis a systematicreview andmeta-analysisrdquo Evidence-BasedMedicine vol 17 no6 pp 171ndash176 2012

[94] V G Hafez M Bosseila M R Abdel Halim O G ShakerM Kamal and H S Kareem ldquoClinical effects of lsquopioglitazonersquoan insulin sensitizing drug on psoriasis vulgaris and its co-morbidities a double blinded randomized controlled trialx1rdquoJournal of Dermatological Treatment vol 1 pp 1ndash7 2014

[95] N R Trivedi Z Cong A M Nelson et al ldquoPeroxisomeproliferator-activated receptors increase human sebumproduc-tionrdquo Journal of Investigative Dermatology vol 126 no 9 pp2002ndash2009 2006

[96] R Shah A Jindal and N M Patel ldquoAcrochordons as a cuta-neous sign ofmetabolic syndrome a case-control studyrdquoAnnalsof Medical and Health Sciences Research vol 4 no 2 p 2022014

[97] J K Agarwal and P K Nigam ldquoAcrochordon a cutaneous signof carbohydrate intolerancerdquo The Australasian Journal of Der-matology vol 28 no 3 pp 132ndash133 1987

[98] S Demir and Y Demir ldquoAcrochordon and impaired carbohy-drate metabolismrdquo Acta Diabetologica vol 39 no 2 pp 57ndash592002

[99] M Kahana E Grossman A Feinstein M Ronnen M Cohenand M S Millet ldquoSkin tags a cutaneous marker for diabetesmellitusrdquoActaDermato-Venereologica vol 67 no 2 pp 175ndash1771987

[100] N S Scheinfeld ldquoObesity and dermatologyrdquo Clinics in Derma-tology vol 22 no 4 pp 303ndash309 2004

[101] N S A A Fattah and Y W Darwish ldquoAndrogenetic alopeciaand insulin resistance are they truly associatedrdquo InternationalJournal of Dermatology vol 50 no 4 pp 417ndash422 2011

[102] G Severi R Sinclair J L Hopper et al ldquoAndrogenetic alopeciain men aged 40ndash69 years prevalence and risk factorsrdquo TheBritish Journal of Dermatology vol 149 no 6 pp 1207ndash12132003

[103] B O Yildiz ldquoDiagnosis of hyperandrogenism clinical criteriardquoBest Practice amp Research Clinical Endocrinology amp Metabolismvol 20 no 2 pp 167ndash176 2006

[104] L Nabaie S Kavand RM Robati N Sarrafi-Rad L Shahgholiand G Meshkat-Razavi ldquoAndrogenic alopecia and insulinresistance are they really relatedrdquo Clinical and ExperimentalDermatology vol 34 no 6 pp 694ndash697 2009


[105] V A Matilainen P Koskela and S Keinanen-KiukaanniemildquoEarly androgenetic alopecia as a marker of insulin resistancerdquoThe Lancet vol 356 no 9236 pp 1165ndash1166 2000

[106] O Bakry M A Shoeib M El Shafiee and A Hassan ldquoAndro-genetic alopecia metabolic syndrome and insulin resistance isthere any association A case-control studyrdquo Indian Dermatol-ogy Online Journal vol 5 no 3 pp 276ndash281 2014

[107] J G Gonzalez-Gonzalez L G Mancillas-Adame M Fernan-dez-Reyes et al ldquoAndrogenetic alopecia and insulin resistancein young menrdquo Clinical Endocrinology vol 71 no 4 pp 494ndash499 2009

[108] C Mumcuoglu T R Ekmekci and S Ucak ldquoThe investigationof insulin resistance and metabolic syndrome in male patientswith early-onset androgenetic alopeciardquo European Journal ofDermatology vol 21 no 1 pp 79ndash82 2011

[109] P Hirsso U Rajala L Hiltunen et al ldquoAssociation of low-insulin sensitivity measured by quantitative insulin sensitivitycheck index with hair loss in 55-year-old men A Finnishpopulation-based studyrdquoDiabetes Obesity andMetabolism vol8 no 4 pp 466ndash468 2006

[110] R Horton V Pasupuletti and I Antonipillai ldquoAndrogen induc-tion of steroid 5120572-reductase may be mediated via insulin-likegrowth factor-Irdquo Endocrinology vol 133 no 2 pp 447ndash4511993

[111] C Dessinioti A Katsambas and C Antoniou ldquoHidradenitissuppurrativa (acne inversa) as a systemic diseaserdquo Clinics inDermatology vol 32 no 3 pp 397ndash408 2014

[112] G B E Jemec ldquoClinical practiceHidradenitis suppurativardquoTheNew England Journal of Medicine vol 366 no 2 pp 158ndash1642012

[113] H Kurzen I Kurokawa G B E Jemec et al ldquoWhat causeshidradenitis suppurativardquo Experimental Dermatology vol 17no 5 pp 455ndash456 2008

[114] B J Harrison G F Read and L E Hughes ldquoEndocrine basisfor the clinical presentation of hidradenitis suppurativardquo BritishJournal of Surgery vol 75 no 10 pp 972ndash975 1988

[115] R L Rosenfield ldquoHirsutismrdquoTheNew England Journal of Medi-cine vol 353 no 24 pp 2578ndash2588 2005

[116] R Azziz E Carmina andM E Sawaya ldquoIdiopathic hirsutismrdquoEndocrine Reviews vol 21 no 4 pp 347ndash362 2000

[117] K Unluhizarci Y Karababa F Bayram and F Kelestimur ldquoTheinvestigation of insulin resistance in patients with idiopathichirsutismrdquoThe Journal of Clinical Endocrinology ampMetabolismvol 89 no 6 pp 2741ndash2744 2004

[118] N S Abdel Fattah and YW Darwish ldquoIs there a role for insulinresistance in nonobese patients with idiopathic hirsutismrdquoTheBritish Journal of Dermatology vol 160 no 5 pp 1011ndash10152009

[119] K A Seetharam ldquoAlopecia areata an updaterdquo Indian Journal ofDermatology Venereology and Leprology vol 79 no 5 pp 563ndash575 2013

[120] S A Muller and R K Winkelmann ldquoAlopecia areata An eva-luation of 736 patientsrdquo Archives of Dermatology vol 88 no 3pp 290ndash297 1963

[121] A S Karadag D T Ertugrul S G Bilgili Z Takci E TutalandH Yilmaz ldquoInsulin resistance is increased in alopecia areatapatientsrdquo Cutaneous and Ocular Toxicology vol 32 no 2 pp102ndash106 2013

[122] J Akrem A Baroudi T Aichi F Houch andM H HamdaouildquoProfile of vitiligo in the south of Tunisiardquo International Journalof Dermatology vol 47 no 7 pp 670ndash674 2008

[123] A S Karadag E Tutal and D T Ertugrul ldquoInsulin resistance isincreased in patients with vitiligordquoActaDermato-Venereologicavol 91 no 5 pp 541ndash544 2011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

View publication statsView publication stats

Review ArticleInsulin Resistance and Skin Diseases

Maddalena Napolitano Matteo Megna and Giuseppe Monfrecola

Section of Dermatology Department of Medicina Clinica e Chirurgia University Federico II Napoli Italy

Correspondence should be addressed to Maddalena Napolitano maddynapolitanogmailcom

Received 18 February 2015 Accepted 17 March 2015

Academic Editor Uwe Wollina

Copyright copy 2015 Maddalena Napolitano et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

In medical practice almost every clinician may encounter patients with skin disease However it is not always easy for physiciansof all specialties to face the daily task of determining the nature and clinical implication of dermatologic manifestations Are theyconfined to the skin representing a pure dermatologic event Or are they alsomarkers of internal conditions relating to the patientrsquosoverall health In this review we will discuss the principal cutaneous conditions which have been linked to metabolic alterationsParticularly since insulin has an important role in homeostasis and physiology of the skinwewill focus on the relationships betweeninsulin resistance (IR) and skin diseases analyzing strongly IR-associated conditions such as acanthosis nigricans acne andpsoriasis without neglecting emerging and potential scenarios as the ones represented by hidradenitis suppurativa androgeneticalopecia and hirsutism

1 Introduction

The skin is the major border organ of human body beingthe most exposed to environmental variations However italso offers a window to what is going on inside the bodyso that changes to the skin may signal a more serioushealth problem frequently serving as amarker for underlyinginternal disease [1 2] Numerous internal diseases are ableto present cutaneous manifestations which may precedeoccur concurrently with or follow the onset of the internalconditions There are a huge number of studies regardingthe relationship of the most common skin manifestations ofinternal diseases (eg diabetes inflammatory bowel diseaseslupus erythematosus systemic sclerosis and tumors) [1 2]However the surveys regarding the relationship betweenmetabolic alterations such as insulin resistance (IR) anddermatologic conditions are still scant

In this review we will discuss the principal skin diseasesand dermatological conditions which have been linked toIR analyzing the mechanisms of the connections betweencutaneous and metabolic deregulations (Table 1)

2 Insulin Insulin Resistance and Skin

Insulin a polypeptide hormone produced by the beta cellsof the islets of Langerhans of the pancreas controls the level

of the glucose in the blood so is a central player in themetabolic system Insulin binding to the insulin receptorleads to receptor autophosphorylation and recruitment ofadaptormolecules such as insulin receptor substrates (IRS 1ndash6)or Shc which are in turn phosphorylated and serve as bindingsites to initiate the activation of different signaling cascadesincluding the mitogen-activated protein kinase (MAPK) andphosphoinositide 3-kinase (PI3-K) pathways [3]These path-ways not only regulate glucose lipid and proteinmetabolismbut also control mitogenic responses through the controlof proliferation differentiation and apoptosis (Figure 1)Insulin signaling is downregulated through inhibitory serinephosphorylation of IRS 1 thus rendering the cells resistantto insulin Interestingly inflammatory mediators such ascytokines can induce IR through the activation of IRS kinases[4] Furthermore insulin has an important role in homeosta-sis and physiology of the skin although the exact functionof insulin signaling remains controversial Under healthyconditions insulin regulates the equilibrium between pro-liferation and differentiation of keratinocytes a prerequisitefor the formation of the epidermal structure Under con-ditions of chronic inflammation (eg acne or psoriasis)high levels of proinflammatory cytokines activate p38MAPKwhich induces IR by serine phosphorylation of IRS leadingto blockade of differentiation and at the same time to

Hindawi Publishing Corporatione Scientific World JournalVolume 2015 Article ID 479354 11 pageshttpdxdoiorg1011552015479354


Insulin

IRS

PI3K

Akt

GSK-3mTORC 1

Ras

Mek

MAP kinase


Cell growth


GLUT 4

GLUT 4

Glucose

S6K1

IGF 1




P

PP

P P PP

P

vesicle

differentiation









with IR





Hyperandrogenism




Genes


Insulin resistance


LH release


darr SHBG





























7 Conclusions






References






































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















Insulin

IRS

PI3K

Akt

GSK-3mTORC 1

Ras

Mek

MAP kinase


Cell growth


GLUT 4

GLUT 4

Glucose

S6K1

IGF 1




P

PP

P P PP

P

vesicle

differentiation









with IR





Hyperandrogenism




Genes


Insulin resistance


LH release


darr SHBG





























7 Conclusions






References






































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















with IR





Hyperandrogenism




Genes


Insulin resistance


LH release


darr SHBG





























7 Conclusions






References






































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of










































7 Conclusions






References






































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





































7 Conclusions






References






































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































7 Conclusions






References






































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























7 Conclusions






References






































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of











































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of










































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Date post:	01-Oct-2020
Category:	Documents
Upload:	others
View:	0 times
Download:	0 times

Insulin Resistance and Skin Diseases · in adolescence and in female gender and is commonly...

Documents