serum leptin, adiponectin, and resistin among adult patients with acanthosis nigricans: correlations...

Report

Serum leptin, adiponectin, and resistin among adult patients

with acanthosis nigricans: correlations with insulin

resistance and risk factors for cardiovascular disease

Mona Atwa1, MD, Amany Emara2, MD, Mona Balata3, MD, Nahed Youssef4, MD,Nervana Bayoumy5, MD, Abdulsalam Sherif6, MD, and Lamia Fiala7, MD

1Department of Dermatology and

Venereology, Suez Canal University,

Ismailia, 2Department of Clinical Pathology,

Ain Shams University, Cairo, 3Department

of Physical Medicine, Rheumatology and

Rehabilitation, Ain Shams University, Cairo,4Department of Clinical Pathology, Suez

Canal University, Ismailia, Egypt,5Department of Physiology, College of

Medicine, King Saud University, Riyadh,

Saudi Arabia, 6Department of Cardiology,

Zagazig University, Zagazig, and7Department of Community and

Occupational Medicine, Suez Canal

University, Ismailia, Egypt

Correspondence

Mona Atwa, MD

Faculty of Medicine

Department of Dermatology and

Venereology

Suez Canal University

Ring Road, Ismailia 11235, Egypt

E-mail: [email protected]

Funding: None.

Conflicts of interest: None.

doi: 10.1111/ijd.12340

Abstract

Background Acanthosis nigricans (AN) is linked to obesity and insulin resistance. Major

adipokines such as leptin, adiponectin, and resistin are known to be dysregulated in

obesity and are key players in the pathogenesis of metabolic syndrome.

Objectives This study was conducted to assess serum levels of the major adipokines

leptin, adiponectin, and resistin, and to study their correlations with the state of insulin

resistance and other risk factors for cardiovascular disease (CVD) among AN patients.

Methods A total of 115 adult subjects were included in the study; 52 of these had benign

acquired AN, and 63 (control subjects) were without AN. Thirty-three of the control group

were obese, and 30 were healthy subjects of normal weight. Body mass index (BMI), blood

pressure, lipid profile, fasting blood glucose, fasting insulin, serum leptin, adiponectin, and

resistin were assessed in all subjects.

Results We found significant differences between AN patients and obese controls in serum

levels of leptin (30.02 � 15.14 ng/ml vs. 21.07 � 7.92 ng/ml; P = 0.002), adiponectin

(5.55 � 2.89 lg/l vs. 9.02 � 2.33 lg/ml; P = 0.00001), and resistin (20.88 � 3.97 ng/ml

vs. 16.82 � 4.36 ng/ml; P = 0.00003). Significant positive correlations were found between

serum leptin and homeostasis model assessment (HOMA) value, insulin, glucose, BMI,

cholesterol, and low-density lipoprotein. There were also significant negative correlations

between adiponectin and HOMA value, insulin, BMI, cholesterol, and leptin among AN

patients.

Conclusions Acanthosis nigricans is a likely forerunner of the finding of metabolic

syndrome. High serum leptin and resistin and low serum adiponectin may increase the risk

for CVD among AN patients.

Introduction

Acanthosis nigricans (AN) is the most common dermato-logic manifestation of obesity. It appears as symmetrical,velvety, hyperpigmented plaques that may occur in almostany location. It is most commonly observed in the axilla,groin, and posterior neck but can also be seen on theelbows, knuckles, and face, particularly in people of dar-ker skin types.1 Pigmented populations in conditions ofplenty are most prone to being affected. The more pig-mented and more obese a population, the higher the fre-quency and the greater the severity of AN.2 Acanthosisnigricans is an important cutaneous finding that may sig-nify internal disease and has been linked to obesity andinsulin resistance with consequent hyperinsulinemia.3–6

Over the last several years, insulin resistance has receivedattention as a possible etiologic factor for dyslipidemia,hypertension, diabetes mellitus type 2 (DM type 2), andcardiovascular disease (CVD).7–10 In obesity, AN is aphysical marker of insulin resistance and of more pro-found metabolic alterations; indeed, AN is frequentlyassociated with metabolic syndrome.11,12

Adipocytokines or adipokines are bioactive productsproduced by adipose tissue (AT). Affecting vascular func-tion, immune regulation, and adipocyte metabolism,adipokines are key players in the pathogenesis of meta-bolic syndrome as a major risk factor for cardiovascularmorbidity and mortality.13

Leptin is a 16-kDa adipokine, mainly produced byadipocytes and expressed in tissues such as placenta,

ª 2013 The International Society of Dermatology International Journal of Dermatology 2013

1

ovaries, skeletal muscle, stomach, pituitary gland, andliver.14 Patients with a leptin deficiency are extremelyobese.15 By contrast, in some obese patients leptin levelsare increased, which has led to the concept of leptin resis-tance in obesity.16 Elevated leptin levels have been associ-ated with the intima-media thickness of the commoncarotid artery,17 and leptin has been proposed as anindependent predictor of future cardiovascular events andcoronary heart disease.18,19

Adiponectin is mainly produced by adipocytes. A nega-tive correlation between body mass index (BMI) andadiponectin plasma levels has been described.20 Adiponec-tin has a regulatory and anti-inflammatory role in athero-sclerosis and is decreased in patients with coronary arterydisease.21 Studies have shown an increased risk forcardiovascular events in patients with low adiponectinlevels.19 Patients with lower levels of adiponectin are alsoat increased risk for the development of DM type 2 andhypertension, as well as dyslipidemia.21,22

Resistin is an AT-derived adipokine which is linked toinflammation, immunity, obesity, and insulin resistance. Inhumans, it is mainly produced by monocytes and macro-phages residing in AT and by peripheral blood monocytes.23

It has been proposed that resistin is linked to the occurrenceof obesity-related insulin resistance and DM type 2.24 Thephysiologic role of resistin in humans remains unknown,and studies have been controversial.25 Resistin was shownto be a predictive factor for coronary atherosclerosis and amarker of the severity of myocardial ischemic injury.26,27

The present study was conducted in an attempt to pro-vide insight into the clinical significance of AN withrespect to adipokines as key contributors in the pathogen-esis of metabolic syndrome, atherosclerosis, and coronaryartery disease. We assessed serum levels of leptin, adipo-nectin, and resistin in patients with AN, compared themwith those in obese and normal-weight control subjects,and correlated them with risk factors for CVD, includingBMI, fasting blood glucose, fasting insulin, insulin resis-tance (evaluated by homeostasis model assessment[HOMA]), cholesterol, and triglycerides.

Materials and methods

Study setting

This was a case–control study conducted in the dermatology

and obesity clinics at Riyadh National Hospital, Riyadh, Saudi

Arabia. The study was approved by the Institutional Review

Board at Riyadh National Hospital and conducted in accordance

with the principles of the Helsinki Declaration.

Subjects

Fifty-two adult AN patients, aged ≥18 years and attending the

dermatology clinic, consented to participate after being given

full information on the set-up and purposes of the study and

were thus enrolled. All patients had benign acquired AN; none

of them were known to have hypertension, diabetes, or

dyslipidemia. Patients who were pregnant, lactating, or had

inflammatory skin diseases, systemic diseases, or malignancy

were excluded from the study. The findings of physical

examinations were normal in all participants, apart from skin

striae and acrochordons in some. Blood pressure (BP), weight,

and height were measured, and BMI was calculated.

The control group included 63 subjects, of whom 33 were

obese (BMI of ≥30 kg/m2) and 30 were of healthy normal

weight. The 33 obese subjects were recruited as a control

group from among patients attending the obesity clinic at

Riyadh National Hospital and were matched for age and

gender with the study group. Patients with DM type 2,

hypertension, or dyslipidemia were excluded. Thus, the same

exclusion criteria were applied to patients and controls.

Physical examination showed that none of the control subjects

had AN.

Table 1 Clinical and laboratory findings in patients withacanthosis nigricans (AN) and obese control subjects

Variable

AN patients

(n = 52)

Obese controls

(n = 30) P-value

Age, years, mean � SD 26.52 � 9.63 29.27 � 7.47 0.12

Sex, n (%)

Males 12 (23.1%) 7 (21.2%) 0.84

Females 40 (76.9%) 26 (78.8%)

Leptin, ng/ml,

mean � SD

30.02 � 15.14 21.07 � 7.92 0.002

Adiponectin, lg/ml,

mean � SD

5.55 � 2.89 9.02 � 2.33 0.00001

Resistin, ng/ml,

mean � SD

20.88 � 3.97 16.82 � 4.36 0.00003

Glucose, mmol/l,

mean � SD

5.47 � 1.44 4.71 � 0.51 0.004

Insulin, lIU/ml,

mean � SD

17.1 � 9.4 11.55 � 3.19 0.001

HOMA, mean � SD 4.56 � 3.89 2.41 � 0.68 0.002

BMI, kg/m2, mean � SD 35.17 � 6.59 31.24 � 1.52 0.001

Cholesterol, mmol/l,

mean � SD

4.77 � 0.89 4.30 � 0.47 0.007

Triglycerides, mmol/l,

mean � SD

1.02 � 0.27 0.91 � 0.28 0.08

LDL, mmol/l,

mean � SD

3.14 � 0.8 2.87 � 0.24 0.06

HDL, mmol/l,

mean � SD

1.21 � 0.27 1.13 � 0.33 0.2

Systole, mmHg,

mean � SD

126.92 � 6.73 120 � 7.91 0.00004

Diastole, mmHg,

mean � SD

82.31 � 4.48 81.21 � 5.45 0.31

SD, standard deviation; HOMA, homeostasis model assess-ment; BMI, body mass index; LDL, low-density lipoprotein;HDL, high-density lipoprotein.

International Journal of Dermatology 2013 ª 2013 The International Society of Dermatology

Report Insulin resistance and cardiovascular disease risk factors in acanthosis nigricans Atwa et al.2

The 30 normal-weight healthy subjects were recruited as a

control group from patients attending the dermatology clinic for

mild skin disease and were matched for age and sex with the

study group. None of them had AN or any other systemic

disease.

A morning serum sample taken after a 12-hour fast was

obtained from all participants for glucose, insulin, and lipid

concentrations including serum total cholesterol, triglycerides,

low-density lipoprotein (LDL) cholesterol, and high-density

lipoprotein (HDL) cholesterol. Total cholesterol, HDL cholesterol,

triglycerides, and fasting blood glucose were measured using

commercial kits from Siemens AG (Dade Behring, Newark, DE,

USA) on a Dade Dimension� Xpand� Clinical Chemistry fully

automated machine (Siemens AG). Levels of LDL were

measured using automated LDL-cholesterol reagent (Siemens

AG) on the same machine. Insulin was measured with a reagent

on an AxSYM machine using a microparticles enzyme

immunoassay (MEIA) with a reagent pack (2D01-21), master

calibrator (2D01-310), and control reference (2D01-11) (Abbott

Laboratories, Inc., Abbott Park, IL, USA). The rate of insulin

resistance was evaluated using the HOMA devised by Matthews

et al.28 and calculated using the formula described by Bonora

et al.29 whereby HOMA = insulin (U/ml) 9 (glucose [mmol/l]/

22.5). Patients were considered to be insulin-resistant when they

showed a HOMA value of ≥2.6.30

Leptin, adiponectin, and resistin assessment

Blood was allowed to clot and, when clotting was complete,

serum was separated by centrifugation and stored in aliquots

at �20 °C. Serum leptin was measured using a commercial kit

(Human Leptin ELISA [KAP2281]; DIAsource ImmunoAssays

SA, Nivelles, Belgium). The analytical sensitivity was 0.04

ng/ml. Serum adiponectin was measured using a commercial kit

(Human Adiponectin ELISA [KAPME09]; DIAsource

Table 2 Clinical and laboratory findings in patients withacanthosis nigricans (AN) and normal-weight control subjects

Variable

AN patients

(n = 52)

Normal-weight

controls (n = 30) P-value

Age, years,

mean � SD

26.52 � 9.63 26.57 � 5.64 0.98

Sex, n (%)

Males 12 (23.1%) 10 (33.3%) 0.31

Females 40 (76.9%) 20 (66.7%)

Leptin, ng/ml,

mean � SD

30.02 � 15.14 6.32 � 6.21 0.00001

Adiponectin, lg/ml,

mean � SD

5.55 � 2.89 21.67 � 17.5 0.00001

Resistin, ng/ml,

mean � SD

20.88 � 3.97 11.87 � 8.43 0.00001

Glucose, mmol/l,

mean � SD

5.47 � 1.44 4.31 � 0.71 0.00001

Insulin, lIU/ml,

mean � SD

17.1 � 9.4 8.0 � 1.91 0.00001

HOMA, mean � SD 4.56 � 3.89 1.52 � 0.46 0.00005

BMI, kg/m2,

mean � SD

35.17 � 6.59 20.73 � 0.94 0.00001


mean � SD

4.77 � 0.89 4.53 � 0.51 0.01


mean � SD

1.02 � 0.27 0.96 � 0.32 0.03

LDL, mmol/l,

mean � SD

3.14 � 0.8 2.88 � 0.22 0.09

HDL, mmol/l,

mean � SD

1.21 � 0.27 1.32 � 0.44 0.17

Systole, mmHg,

mean � SD

126.92 � 6.73 116.67 � 6.07 0.00001

Diastole, mmHg,

mean � SD

82.31 � 4.48 79.67 � 1.27 0.002


Table 3 Clinical and laboratory findings in obese andnormal-weight control subjects

Variable

Obese controls

(n = 33)

Normal-weight

controls (n = 30) P-value

Age, years,

mean � SD

29.27 � 7.47 26.57 � 5.64 0.11

Sex, n (%)

Males 7 (21.2%) 10 (33.3%) 0.27

Females 26 (78.8%) 20 (66.7%)

Leptin, ng/ml,

mean � SD

21.07 � 7.92 6.32 � 6.21 0.00001

Adiponectin, lg/ml,

mean � SD

9.02 � 2.33 21.67 � 17.5 0.0001

Resistin, ng/ml,

mean � SD

16.82 � 4.36 11.87 � 8.43 0.001

Glucose, mmol/l,

mean � SD

4.71 � 0.51 4.31 � 0.71 0.01

Insulin, lIU/ml,

mean � SD

11.55 � 3.19 8.0 � 1.91 0.00002

HOMA, mean � SD 2.41 � 0.68 1.52 � 0.46 0.00001

BMI, kg/m2,

mean � SD

31.24 � 1.52 20.73 � 0.94 0.00001


mean � SD

4.30 � 0.47 4.53 � 0.51 0.065


mean � SD

0.91 � 0.28 0.96 � 0.32 0.56

LDL, mmol/l,

mean � SD

2.87 � 0.24 2.88 � 0.22 0.85

HDL, mmol/l,

mean � SD

1.13 � 0.33 1.32 � 0.44 0.10

Systole, mmHg,

mean � SD

120 � 7.91 116.67 � 6.07 0.06

Diastole, mmHg,

mean � SD

81.21 � 5.45 79.67 � 1.27 0.13



Atwa et al. Insulin resistance and cardiovascular disease risk factors in acanthosis nigricans Report 3

ImmunoAssays SA). Analytical sensitivity was <0.6 ng/ml.

Serum resistin was measured using a commercial kit (Human

Resistin ELISA [KAPME50]; DIAsource ImmunoAssays SA).

Analytical sensitivity was 0.012 ng/ml. All three tests were run

on a Personal LAB machine (Adaltis Srl, Rome, Italy).

Statistical analysis

Data were analyzed using SPSS Version 17.0 (SPSS, Inc.,

Chicago, IL, USA). Frequency tables were produced; Student’s

t-test was used to test differences in quantitative variables,

and the chi-squared test was used for categorical variables.

Pearson’s correlation coefficient (r) was used to test correlations

of any two continuous variables.

Results

Fifty-two patients with AN were included in this study; 40were female and 12 were male. Their mean � standarddeviation (SD) age was 26.52 � 9.63 years, and theirmean � SD BMI was 35.17 � 6.59 kg/m2. Table 1 com-

pares data for AN patients and obese control subjectswithout AN, respectively. There was no statistically signifi-cant difference between the two groups in age, gender,serum triglycerides, LDL, HDL, or diastolic BP. By con-trast, we found statistically significant differences betweenAN patients and obese control subjects without AN inmean � SD serum leptin (30.02 � 15.14 ng/ml vs.21.07 � 7.92 ng/ml; P = 0.002), serum adiponectin(5.55 � 2.89 lg/ml; vs. 9.02 � 2.33 lg/ml; P = 0.00001),and serum resistin (20.88 � 3.97 ng/ml vs. 16.82 �4.36 ng/ml; P < 0.001) (Table 1). We also noted statisti-cally significant differences between patients with ANand obese control subjects in fasting serum glucose(P = 0.004), fasting serum insulin (P = 0.001), HOMAvalue (P = 0.002), BMI (P = 0.001), serum cholesterol(P = 0.007), and systolic BP (P = 0.00004) (Table 1).A comparison of findings in AN patients with those in

normal-weight healthy control subjects showed no statisti-cally significant differences in age, gender, or serum LDLand HDL (Table 2). However, serum leptin was signifi-cantly higher in AN patients compared with normal-weightcontrols (30.02 � 15.14 ng/ml vs. 6.32 � 6.21 ng/ml;P < 0.001). We also found statistically significant differ-ences between AN patients and normal-weight controlsubjects in serum adiponectin (5.55 � 2.89 lg/ml vs.21.67 � 17.5 lg/ml; P < 0.001) and serum resistin(20.88 � 3.97 ng/ml vs. 11.87 � 8.43 ng/ml; P < 0.001)(Table 2). Patients with AN differed significantly from nor-mal-weight control subjects without AN in fasting glucose(P < 0.001), fasting insulin (P < 0.001), HOMA value(P < 0.001), BMI (P < 0.001), cholesterol (P = 0.01), tri-glycerides (P = 0.03), systolic BP (P < 0.001), and diastolicBP (P = 0.002) (Table 2).A comparison between obese control subjects and nor-

mal-weight control subjects showed no statistically signifi-cant differences in age, gender, cholesterol, triglycerides,LDL, HDL, systolic BP, or diastolic BP (Table 3). Wefound statistically significant differences between obeseand normal-weight control subjects in leptin (P < 0.001),adiponectin (P < 0.001), resistin (P = 0.001), fasting glu-cose (P = 0.01), fasting insulin (P < 0.001), HOMA value(P < 0.001), and BMI (P < 0.001) (Table 3).Insulin resistance (HOMA ≥2.6) was noted in 34

(65.4%) of the 52 patients with AN, 17 (51.5%) of the33 obese control subjects without AN, and none of the30 normal-weight healthy control subjects. This differ-ence in insulin resistance was statistically significant(P < 0.001). Patients with AN were 1.78 times morelikely to have insulin resistance than obese control sub-jects without AN (95% confidence interval 0.67–4.7;P = 0.2). None of the obese control subjects without ANor normal-weight healthy control subjects had diabetesor hyperinsulinemia (insulin ≥1731), whereas eight

Table 4 Clinical and laboratory findings in patients withacanthosis nigricans (AN) with and without insulin resistance

Variable

AN without

insulin

resistance

(n = 18)

AN with

insulin

resistance

(n = 34) P-value

Age, years, mean � SD 21.17 � 3.79 29.35 � 10.58 0.003

Sex, n (%)

Males 6 (33.3%) 6 (17.6%) 0.20

Females 12 (66.7%) 28 (82.4%)

Leptin, ng/ml,

mean � SD

25.44 � 14.79 32.43 � 14.97 0.114

Adiponectin, lg/ml,

mean � SD

6.54 � 2.73 5.01 � 2.87 0.068

Resistin, ng/ml,

mean � SD

21.34 � 4.01 20.87 � 4.01 0.69

Glucose, mmol/l,

mean � SD

4.58 � 0.36 5.94 � 1.57 0.001

Insulin, lIU/ml,

mean � SD

9.70 � 2.80 20.94 � 9.19 0.001

BMI, kg/m2, mean � SD 33.39 � 6.67 36.12 � 6.44 0.157


mean � SD

4.45 � 0.69 4.97 � 0.92 0.041


mean � SD

0.83 � 0.25 1.13 � 0.23 0.0001

LDL, mmol/l, mean � SD 2.82 � 0.42 3.30 � 0.90 0.035

HDL, mmol/l,

mean � SD

1.31 � 0.28 1.15 � 0.25 0.040

Systole, mmHg,

mean � SD

125.56 � 7.05 127.65 � 6.54 0.291

Diastole, mmHg,

mean � SD

81.11 � 3.23 82.94 � 4.94 0.163

SD, standard deviation; BMI, body mass index; LDL, low-density lipoprotein; HDL, high-density lipoprotein.



Table

5Correlation

matrixshow

ingPearsons

ran

dP-valuesforstud

yva

riab

lesam

ongpa

tients

withacan

thosis

nigrican

s

Leptin

Adiponectin

Resistin

Glucose

Insulin

HOMA

BMI

Cholesterol

Triglycerides

LDL

HDL

SystolicBP

DiastolicBP

Age

r0.133

0.079

0.100

0.698

0.331

0.471

0.222

0.333

0.307

0.370

0.042

0.331

0.117

P-value

00.347

0.580

0.479

0.30

0.017

0.30

0.114

0.016

0.027

0.007

0.765

0.017

0.408

Leptin

r�0

.452

0.077

0.351

0.403

0.416

0.319

0.447

0.151

0.443

0.203

�0.364

�0.149

P-value

0.001

0.586

0.011

0.003

0.002

0.021

0.001

0.284

0.001

0.148

0.008

0.290

Adiponectin

r�0

.118

�0.266

�0.417

�0.362

�0.290

�0.411

�0.101

�0.186

0.063

0.288

0.056

P-value

0.406

0.057

0.002

0.008

0.037

0.002

0.477

0.186

0.655

0.039

0.695

Resistin

r0.216

0.111

0.152

0.252

0.076

0.055

�0.006

0.007

�0.189

�0.115

P-value

0.124

0.434

0.283

0.071

0.591

0.698

0.969

0.960

0.179

0.417

Glucose

r0.703

0.857

0.290

0.533

0.288

0.481

0.130

0.197

0.308

P-value

0.30

0.30

0.037

0.30

0.038

0.30

0.357

0.162

0.026

Insulin

r0.946

0.248

0.551

0.310

0.324

0.050

0.163

0.340

P-value

0.000

0.076

0.30

0.025

0.019

0.724

0.247

0.014

HOMA

r0.254

0.611

0.277

0.449

0.161

0.158

0.361

P-value

0.069

0.31

0.047

0.001

0.254

0.265

0.009

BMI

r0.337

0.086

0.144

0.018

0.056

0.335

P-value

0.015

0.547

0.309

0.899

0.691

0.015

Cholesterol

r0.200

0.696

0.373

-0.042

0.043

P-value

0.155

0.30

0.007

0.766

0.761

Triglycerides

r0.161

�0.063

�0.158

�0.182

P-value

0.253

0.655

0.264

0.196

LDL

r0.254

0.006

0.076

P-value

0.070

0.968

0.592

HDL

r�0

.139

�0.185

P-value

0.326

0.190

Systolic

BP

r0.468

P-value

0.000

HOM

A,ho

meostasis

mod

elassessment;BM

I,bo

dymassindex;

LDL,low-density

lipop

rotein;HDL,high

-density

lipop

rotein;BP,

bloo

dpressure.



(15.4%) of the AN patients had diabetes and 20 (38.5%)had hyperinsulinemia. We also found hypercholesterol-emia in 18 (34.6%) AN patients, none of the obese con-trol subjects, and four (13.3%) of the normal-weightcontrols. This difference in hypercholesterolemia was sta-tistically significant (P < 0.001). Table 4 compares datain AN patients with and without insulin resistance. Therewere no statistically significant differences between ANpatients with and without insulin resistance in gender,serum leptin, adiponectin, resistin, BMI, or BP. Acantho-sis nigricans patients with insulin resistance differed sig-nificantly from AN patients without insulin resistance inage (P = 0.003), fasting glucose (P = 0.001), fasting insu-lin (P = 0.001), cholesterol (P = 0.041), triglycerides(P < 0.001), LDL (P = 0.035), and HDL (P = 0.040)(Table 4).The correlations of the serum adipokines leptin, adipo-

nectin, and resistin, with the insulin resistance index

(HOMA) and other CVD risk factors among AN patients,are shown in Table 5. There were statistically significantpositive correlations between serum leptin and HOMA(r = 0.416, P = 0.002), fasting insulin (r = 0.403, P =0.003), and fasting glucose (r = 0.351, P = 0.011). We alsofound statistically significant positive correlations betweenserum leptin and BMI (r = 0.319, P = 0.021), cholesterol(r = 0.447, P = 0.001), and LDL (r = 0.443, P = 0.001)(Table 5, Fig. 1). There was a statistically significant nega-tive correlation between serum leptin and serum adiponec-tin (r = �0.452, P = 0.001) (Table 5, Fig. 2).With reference to serum adiponectin, statistically signifi-

cant negative correlations emerged between adiponectinand HOMA (r = � 0.362, P = 0.008), fasting insulin(r = �0.417, P = 0.002), BMI (r = �0.290, P = 0.037),and cholesterol (r = �0.411, P = 0.002) among ANpatients (Table 5, Fig. 3). There was a statisticallyinsignificant negative correlation between serum adiponec-

Lep

tin

, ng

/mL

Lep

tin

, ng

/mL

HOMA Body mass index, kg/m2

Cholesterol, mmol/L Triglycerides, mmol/L

Lep

tin

, ng

/mL

Lep

tin

, ng

/mL

(a) (b)

(c) (d)

Figure 1 Correlations between serum leptin and (a) homeostasis model assessment (HOMA) value, (b) body mass index, (c)cholesterol and (d) triglycerides in acanthosis nigricans patients



tin and serum resistin (r = �0.118, P = 0.406). We alsofound correlations between serum resistin and HOMA,fasting insulin, fasting glucose, and BMI, although thesewere statistically insignificant (Table 5, Fig. 4).

Discussion

Obesity is a common problem in Saudi Arabia and occursat an overall prevalence of 35.6%,32 which explains thehigh prevalence of AN in the country. Acanthosis nigri-cans is the most common dermatologic manifestation ofobesity. As the frequency and degree of obesity increasein a population, a concomitant increase in AN can beexpected.33,34 Hud et al.35 found that 74% of an obesepopulation exhibited AN along with elevated plasmainsulin levels. In the present study, patients with AN hadsignificantly higher BMI than obese control subjects with-out AN. This is in agreement with the results of otherstudies that have reported the BMI of subjects with ANto be significantly greater than that in subjects withoutAN.36–39

Hyperinsulinemia, a consequence of the insulin resis-tance that occurs in association with obesity, stimulatesthe formation of AN.4–6 The results of the present studyshowed hyperinsulinemia in 38.5% of adult patients withAN. Similar results have been found in other studies inwhich AN was associated in some cases with hyperinsulin-emia.3,12,35,40–42 In line with other studies,12,35,37,41,43,44

the present findings indicated that 65.4% of AN patientshad insulin resistance, and 15.4% had diabetes. Theseresults may suggest that AN is associated with insulinresistance and hyperinsulinemia in a substantial propor-tion of adult patients; both are major factors in the patho-physiology of DM type 2. The clinical detection of ANmay help to identify individuals at high risk for DM type2, which is a major risk factor for CVD.Adipokines are key contributors in the pathogenesis of

metabolic syndrome, which is a major risk factor for car-diovascular morbidity and mortality.13 In the presentstudy of adult patients with AN, we wanted to assessserum levels of the major adipokines leptin, adiponectin,and resistin and to determine their correlations with levelsof insulin resistance and other risk factors for CVD. Wefound that serum leptin was significantly higher in ANpatients than in either obese or normal-weight controlsubjects without AN, and there were statistically signifi-cant positive correlations between serum leptin and CVDrisk factors including HOMA, fasting insulin, fastingglucose, BMI, and cholesterol. These findings are consis-tent with those of Bonet and associates, who found thatserum leptin was higher in obese children with ANthan in obese children without AN and was positively

Lep

tin

, ng

/mL

L

epti

n, n

g/m

L

Resistin, ng/mL

Resistin, ng/mL

Adiponectin, µg/mL

Ad

ipo

nec

tin

, µg

/mL

(a)

(b)

(c)

Figure 2 Correlations between serum (a) leptin and resistin,(b) adiponectin and resistin and (c) leptin and adiponectin inacanthosis nigricans patients



correlated with BMI.45 However, the correlation of serumleptin with other CVD risk factors was not studied. Simi-larly, Miura et al.38 reported that serum leptin was signif-icantly higher in obese children and adolescents with ANthan in obese control subjects. Leptin was proposed to bean independent predictor of future cardiovascular eventsand coronary heart disease.18,19 Hence, the present resultsmay suggest that adult patients with AN are at higherrisk for CVD.In this study, adiponectin was significantly decreased in

patients with AN in comparison with obese and normal-weight controls, and there were statistically significantnegative correlations between serum adiponectin andCVD risk factors including HOMA, fasting insulin, BMI,and cholesterol. This is in agreement with Bonet et al.,who found that serum adiponectin was significantlydecreased in children with AN in comparison with obese

children without AN and was negatively correlated withBMI.45 A negative correlation between BMI and adipo-nectin plasma levels has been described,20 and patientswith lower levels of adiponectin are also at increased riskfor the development of DM type 2 and hypertension aswell as dyslipidemia.21,22 Given that previous researchhas also shown an increased risk for cardiovascularevents in patients with low adiponectin levels,19 the find-ings of the present study indicate that risk for CVD maybe increased in adult patients with AN.In the present study, serum resistin was significantly

higher in AN than in obese or normal-weight control sub-jects. However, no significant correlation between serumresistin and HOMA or other CVD risk factors emerged.To our knowledge, no previous studies have investigatedresistin in AN patients. The physiologic role of resistinin humans remains unknown, and studies of it have

Ad

ipo

nec

tin

, µg

/mL

Ad

ipo

nec

tin

, µg

/mL

Ad

ipo

nec

tin

, µg

/mL

Ad

ipo

nec

tin

, µg

/mL



(a) (b)

(c) (d)

Figure 3 Correlations between serum adiponectin and (a) homeostasis model assessment (HOMA) value, (b) body mass index,(c) cholesterol and (d) triglycerides in acanthosis nigricans patients



produced controversial findings.25 However, evidencesuggests that resistin is involved in pathologic processesleading to CVD, including inflammation, endothelialdysfunction, thrombosis, angiogenesis, and smooth mus-cle cell dysfunction.26,27 In the present study, the findingof higher serum levels of resistin in AN patients indicatesthat it may play a role in the pathogenesis of AN. Morestudies including greater numbers of AN patients areneeded to explore the role of resistin in AN and itsrelation to risk for CVD.In conclusion, the main finding of this study was that

AN is associated with hyperinsulinemia, insulin resis-tance, higher BMI, higher cholesterol, and higher systolicBP. This may suggest that AN may be a forerunner find-ing of metabolic syndrome, which is a major risk factorfor cardiovascular morbidity and mortality. High serumlevels of leptin and resistin and a low serum level of

adiponectin may increase the risk for CVD among ANpatients.

References

1 Yosipovitch G, DeVore A, Dawn A. Obesity and the skin:skin physiology and skin manifestations of obesity. J AmAcad Dermatol 2007; 56: 901–916.

2 Maitra SK, Payne CMER. The obesity syndrome andacanthosis nigricans. Acanthosis nigricans is a commoncosmetic problem providing epidemiological clues to theobesity syndrome, the insulin-resistance syndrome, thethrifty metabolism, dyslipidemia, hypertension anddiabetes mellitus type II. J Cosmet Dermatol 2004; 3:202–210.

3 Stuart CA, Smith MM, Gilkison CR, et al. Acanthosisnigricans among Native Americans: an indicator of highdiabetes risk. Am J Public Health 1994; 84: 1839–1842.

Res

isti

n, n

g/m

LR

esis

tin

, ng

/mL

Res

isti

n, n

g/m

LR

esis

tin

, ng

/mL



(a) (b)

(c) (d)

Figure 4 Correlations between serum resistin and (a) homeostasis model assessment (HOMA) value, (b) body mass index, (c)cholesterol and (d) triglycerides in acanthosis nigricans patients



4 Davidson MB. Clinical implications of insulin resistancesyndromes. Am J Med 1995; 99: 420–426.

5 Moller DE, Flier JS. Insulin resistance – mechanisms,syndromes, and implications. New Engl J Med 1991;325: 938–948.

6 Cruz PD Jr, Hud JA Jr. Excess insulin binding to insulin-like growth factor receptors: proposed mechanism foracanthosis nigricans. J Investig Dermatol 1992; 98(6Suppl.): 82–85.

7 Suzuki M, Odaka H. Hypertension and insulin resistancein obese type 2 diabetic Wistar fatty rat. Nippon Rinsho

2003; 61: 1119–1123.8 Reaven GM. Banting lecture. Role of insulin resistance in

human disease. Diabetes 1988; 37: 1595–1607.9 Laakso M. Insulin resistance and coronary heart disease.

Curr Opin Lipidol 1996; 7: 217–226.10 Stern MP. Do non-insulin-dependent diabetes mellitus

and cardiovascular disease share common antecedents?Ann Intern Med 1996; 124: 110–116.

11 Nguyen TT, Keil MF, Russell DL, et al. Relation ofacanthosis nigricans to hyperinsulinemia and insulinsensitivity in overweight African American and Whitechildren. J Pediatr 2001; 138: 474–480.

12 Kobaissi HA, Weigensberg MJ, Ball GDC, et al. Relationbetween acanthosis nigricans and insulin sensitivity inoverweight Hispanic children at risk for type 2 diabetes.Diabetes Care 2004; 27: 1412–1416.

13 Guzik TJ, Mangalat D, Korbut R. Adipocytokines –novel link between inflammation and vascular function? J

Physiol Pharmacol 2006; 57: 505–528.14 Koerner A, Kratzsch J, Kiess W. Adipocytokines: leptin –

the classical, resistin – the controversial, adiponectin –the promising, and more to come. Best Pract Res ClinEndocrinol Metab 2005; 19: 525–546.

15 Farooqi IS, Jebb SA, Langmack G, et al. Effects ofrecombinant leptin therapy in a child with congenitalleptin deficiency. N Engl J Med 1999; 341: 879–884.

16 Guerre-Millo M. Adipose tissue and adipokines: forbetter or worse. Diabetes Metab 2004; 30: 13–19.

17 Ciccone M, Vettor R, Pannacciulli N, et al. Plasma leptinis independently associated with the intima-mediathickness of the common carotid artery. Int J Obes Relat

Metab Disord 2001; 25: 805–810.18 Wolk R, Berger P, Lennon RJ, et al. Plasma leptin and

prognosis in patients with established coronaryatherosclerosis. J Am Coll Cardiol 2004; 44: 1819–1824.

19 Wallace AM, McMahon AD, Packard CJ, et al. Plasmaleptin and the risk of cardiovascular disease in the westof Scotland coronary prevention study (WOSCOPS).Circulation 2001; 104: 3052–3056.

20 Yang WS, Lee WJ, Funahashi T, et al. Weight reductionincreases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol

Metab 2001; 86: 3815–3819.21 Okamoto Y, Kihara S, Funahashi T, et al. Adiponectin: a

key adipocytokine in metabolic syndrome. Clin Sci

(Lond) 2006; 110: 267–278.

22 Iwashima Y, Katsuya T, Ishikawa K, et al.Hypoadiponectinemia is an independent risk factor forhypertension. Hypertension 2004; 43: 1318–1323.

23 McTernan CL, McTernan PG, Harte AL, et al. Resistin,central obesity, and type 2 diabetes. Lancet 2002; 359:46–47.

24 Mora-Janiszewska O, Kulik-Rechberger B, Rechberger T.The role of insulin resistance and resistin in pathogenesisof diabetes mellitus with special attention to diabetes inpregnancy. Ginekol Pol 2005; 76: 580–585.

25 Anderlova K, Kremen J, Dolezalova R, et al. Theinfluence of very-low-calorie-diet on serum leptin, solubleleptin receptor, adiponectin and resistin levels in obesewomen. Physiol Res 2006; 55: 277–283.

26 Reilly MP, Lehrke M, Wolfe ML, et al. Resistin is aninflammatory marker of atherosclerosis in humans.Circulation 2005; 111: 932–939.

27 Chu S, Ding W, Li K, et al. Plasma resistin associatedwith myocardium injury in patients with acute coronarysyndrome. Circ J 2008; 72: 1249–1253.

28 Matthews DR, Hosker JP, Rudenski AS, et al.Homeostasis model assessment. Insulin resistance andbeta-cell function from fasting plasma glucose and insulinconcentrations in man. Diabetologia 1985; 28: 412–419.

29 Bonora E, Targher G, Alberiche M, et al. Homeostasismodel assessment closely mirrors the glucose clamptechnique in the assessment of insulin sensitivity: studiesin subjects with various degrees of glucose tolerance andinsulin sensitivity. Diabetes Care 2000; 23: 57–63.

30 McAuley KA, Williams SM, Mann JI, et al. Diagnosinginsulin resistance in the general population. Diabetes

Care 2001; 24: 460–464.31 Lin TC, Yen JM, Gong KP, et al. Abnormal glucose

tolerance and insulin resistance in polycystic ovarysyndrome amongst the Taiwanese population – notcorrelated with insulin receptor substrate-1 Gly972Arg/Ala513Pro polymorphism. BMC Med Genet 2006; 7: 1-8.

32 Al-Nozha MM, Al-Mazrou YY, Al-Maatouq MA, et al.Obesity in Saudi Arabia. Saudi Med J 2005; 26:824–829.

33 Mei Z, Scanlon KS, Grummer-Strawn LM, et al.Increasing prevalence of overweight among US low-income preschool children: the Centers for DiseaseControl and Prevention pediatric nutrition surveillance,1983 to 1995. Pediatrics 1998; 101: 112.

34 Heini AF, Weinsier RL. Divergent trends in obesity andfat intake patterns: the American paradox. Am J Med

1997; 102: 259–264.35 Hud JA Jr, Cohen JB, Wagner JM, et al. Prevalence and

significance of acanthosis nigricans in an adult obesepopulation. Arch Dermatol 1992; 128: 941–944.

36 Hirschler V, Aranda C, Oneto A, et al. Is acanthosisnigricans a marker of insulin resistance in obese children?Diabetes Care 2002; 25: 2353.

37 Yamazaki H, Ito S, Yoshida H. Acanthosis nigricans isa reliable cutaneous marker of insulin resistance in



obese Japanese children. Pediatr Int 2003; 45: 701–705.

38 Miura N, Ikezaki A, Iwama S, et al. Genetic factors andclinical significance of acanthosis nigricans in obeseJapanese children and adolescents. Acta Paediatr 2006;95: 170–175.

39 Guran T, Turan S, Akcay T, et al. Significance ofacanthosis nigricans in childhood obesity. J PaediatrChild Health 2008; 44: 338–341.

40 Litonjua P, Pinero-Pilona A, Aviles-Santa L, et al.Prevalence of acanthosis nigricans in newlydiagnosed type 2 diabetes. Endocr Pract 2004; 10:101–106.

41 Mukhtar Q, Cleverley G, Voorhees RE, et al. Prevalenceof acanthosis nigricans and its association withhyperinsulinemia in New Mexico adolescents. J AdolescHealth 2001; 28: 372–376.

42 Stoddart ML, Blevins KS, Lee ET, et al. Association ofacanthosis nigricans with hyperinsulinemia comparedwith other selected risk factors for type 2 diabetes inCherokee Indians: the Cherokee Diabetes Study. Diabetes

Care 2002; 25: 1009–1014.43 Copeland K, Pankratz K, Cathey V, et al. Acanthosis

nigricans, insulin resistance (HOMA) and dyslipidemiaamong Native American children. J Okla State Med

Assoc 2006; 99: 19–24.44 Kong AS, Williams RL, Smith M, et al. Acanthosis

nigricans and diabetes risk factors: prevalence in youngpersons seen in southwestern US primary care practices.Ann Fam Med 2007; 5: 202–208.

45 Bonet B, Viana M, S�anchez-Verat I, et al. Adipose tissueand liver lipid metabolism in obese children: role of thebody mass index and the presence of acanthosisnigricans. Diabet Med 2007; 24: 1192–1198.



serum leptin, adiponectin, and resistin among adult patients with acanthosis nigricans: correlations...

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