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ORIGINAL ARTICLE
Year : 2022  |  Volume : 23  |  Issue : 2  |  Page : 105-110

Acanthosis Nigricans: An overt clinical marker of insulin resistance and its association with serum adiponectin levels in obese pediatric population


1 Department of Dermatology, Government Medical College, Patiala, Punjab, India
2 Department of Dermatology, Civil Hospital, Kapurthala, Punjab, India
3 Department of Paediatrics, Government Medical College, Patiala, Punjab, India
4 Department of Biochemistry, Government Medical College, Patiala, Punjab, India

Date of Submission29-Jun-2021
Date of Decision22-Aug-2021
Date of Acceptance03-Dec-2021
Date of Web Publication30-Mar-2022

Correspondence Address:
Dr. Dimple Chopra
No. 27, Bank Colony, Patiala - 147 001, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.ijpd_102_21

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  Abstract 


Background: Childhood obesity (OB) is becoming increasingly prevalent in recent times. Acanthosis nigricans (AN) is a clinical condition linked to OB and insulin resistance (IR). Serum adiponectin is one of the major adipokines that is inversely related to the severity of IR. Objective: The main aim of this study is to evaluate the correlation of severity (grades) of AN with serum adiponectin levels and IR. Materials and Methods: A total of 80 subjects were studied, 50 having OB with AN (OB+AN) and 30 having OB without AN (OB-AN), having age 10–18 years fulfilling the set inclusion and exclusion criteria. Body mass index, fasting blood glucose, HOMA-IR (Homeostatic Model Assessment of IR) and serum adiponectin levels were measured in all subjects. Results: Compared to OB-AN group, OB+AN group had statistically significant lower serum adiponectin levels and higher HOMA-IR values. AN grades correlated positively with HOMA-IR values and negatively with serum adiponectin levels in a statistically significant manner. Conclusion: Grading AN clinically can be easy and useful tool to detect IR in obese subjects. Serum adiponectin levels can be used as another lab parameter in obese subjects guiding the severity of AN.

Keywords: Acanthosis nigricans, adiponectin, insulin resistance, obesity


How to cite this article:
Walia R, Riyat A, Kaur B, Kaur M, Aulakh S, Chopra D. Acanthosis Nigricans: An overt clinical marker of insulin resistance and its association with serum adiponectin levels in obese pediatric population. Indian J Paediatr Dermatol 2022;23:105-10

How to cite this URL:
Walia R, Riyat A, Kaur B, Kaur M, Aulakh S, Chopra D. Acanthosis Nigricans: An overt clinical marker of insulin resistance and its association with serum adiponectin levels in obese pediatric population. Indian J Paediatr Dermatol [serial online] 2022 [cited 2022 May 21];23:105-10. Available from: https://www.ijpd.in/text.asp?2022/23/2/105/341453




  Introduction Top


With the change in lifestyle and dietary patterns, pediatric population is getting more prone to obesity (OB), which can have long-term effect on their health in future. High body mass index (BMI) in childhood is strongly correlated with adulthood OB.[1] Although BMI is not a perfect measure of OB (as it cannot distinguish between lean and fat body mass), it is a reliable way of identifying individuals at risk of weight-related morbidity and mortality.

Acanthosis nigricans (AN) is a skin condition characterized by thickened, coarse, hyperpigmented, and velvety-textured skin present generally on neck and intertriginous areas such as axillae, antecubital and popliteal fossae, and groin folds.[2] AN is classified by Schwartz as OB associated, malignant AN, syndromic AN, medication associated, autoimmune AN, acral AN, nevoid AN, and familial AN.[3]

Adipokines are the bioactive peptide products secreted by white adipose tissue and are key players in pathogenesis of metabolic syndrome (MS). Three main adipokines include leptin (16Kda), adiponectin (30Kda), and resistin.[4] The Adipo Q gene on chromosome locus 3q27 encodes adiponectin and mutation in this gene is associated with adiponectin deficiency.[5] Adiponectin has a regulatory and anti-inflammatory role described in various conditions associated with metabolic disorders.[6]

There exists a negative correlation between adiponectin and BMI and IR. Furthermore, patients with lower levels of adiponectin have been shown have an increased risk of cardiovascular diseases, diabetes mellitus type 2 and hypertension.[7]

In this study, we evaluated the hypothesized negative association between the grades of AN and serum adiponectin levels, to provide clinical correlation of AN with serum adiponectin levels and IR.

Aims and objectives

  1. To determine BMI and serum adiponectin levels in obese pediatric population
  2. To correlate the grades of AN with serum adiponectin levels
  3. To study correlation of IR with AN and serum adiponectin.



  Materials and Methods Top


Study design

This was a cross-sectional study.

Study setting

This study was conducted in a tertiary level hospital in North India between April 2018 and March 2019 after approval from Institutional Ethics Committee (BFUHS/2k18pTH/17416 dated 31/08/2018). Informed consent was taken from the parents of chidren before filling the designated proforma.

Study subjects

Eighty children (10–18 years), all of whom were obese (BMI ≥95th percentile for same age and gender), were included. Fifty subjects were assigned in obese patients with AN (OB+AN) group and 30 subjects taken as control in OB without AN (OB-AN) group. Sampling was done on voluntary basis. Subjects included were the ones who were fulfilling inclusion criteria according to case definitions described below and gave informed consent to participate in the study. Subjects who were having inborn error of metabolism, hypertension, liver, kidney or endocrine disorder, or taking any medications that promote hyperinsulinemia and AN were excluded from the study.

Case definitions

Obese

BMI at or above the 95th percentile for children and teens of the same age and sex. BMI was calculated by the formula weight (kg)/height2 (meters). The Indian Academy of Paediatrics (IAP) BMI charts (5–18 years) for boys and girls were plotted for each subject according to the gender. IAP charts allowed easy diagnosis of OB in Indian subjects according to age and gender.[8]

Acanthosis nigricans

Dark, thick, velvety, and pigmented skin over child's neck and axilla, head and neck region, armpits, breasts, elbow, groin, knees, and knuckles assessed by careful visual examination. Grading of AN to determine severity was done by quantitative scale devised by Burke et al., which include grade 0–4 each for the extent of neck and axilla involvement, and grade 0–3 for neck texture.[9]

Patient assessment

Detailed medical and family history was taken from all subjects. All patients in OB+AN group had benign acquired AN. Patients on steroid therapy, endocrine disorders, hypertension, and history of any malignancy were excluded from the study. The height and weight of each patient were calculated three times and mean of the three values was taken as the final reading.

Assessment of serum parameters

After 12 hours of overnight fasting 5mL of blood samples were taken and stored at − 20°C. Serum blood sugar levels and serum insulin levels were measured using routine methods. Serum adiponectin levels were measured by solid-phase sandwich enzyme immunoassay (Calbiotech® Inc. Adiponectin ELISA kit) and read with LisaScan® EM. HOMA was calculated by the formula HOMA = insulin (U/ml) × Fasting blood sugar (FBS) (mg/dl)/405. HOMA represented rate of IR.[10] We diagnosed IR when the Homeostatic Model Assessment of IR (HOMA-IR) was >2.7.[2]

Statistical analysis

Statistical analysis was done using IBM SPSS software version 22 (SPSS Inc., Chicago, IL, USA). Mean ± standard deviation were calculated for the data for continuous variables and frequencies for categorical variables. Student's t-test was used to assess differences in quantitative variables, Chi-square (χ2) test was used to test the significance of difference between two proportions and P value was calculated to determine if the data was statistically significant. A P ≤ 0.05 was considered statistically significant. Spearman's rank correlation coefficient was used to correlate grades of AN with serum adiponectin levels. Pearson's correlation coefficient was used to analyze linear correlation between continuous variables. Box plot was made and odd's ratio calculated wherever necessary.


  Results Top


All the children in OB+AN and OB-AN group were obese as per growth charts by IAP. The two groups were matched with respect to age and gender. Statistically significant difference (P = 0.006) was found between the BMI of OB+AN (29.19 ± 3.54 kg/m2) and OB-AN (26.99 ± 3.05 kg/m2) [Table 1].
Table 1: Demographic and metabolic profile of obesity + acanthosis nigricans and obesity - acanthosis nigricans groups

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Acanthosis nigricans

The mean age of onset of AN in OB+AN group was 11.64 ± 2.04 years. All patients (100%) had neck involvement and 92% had axilla involvement. Other sites of involvement were antecubital fossa (74%), knuckle AN (64%), groins (50%), and knees (48%). Majority of patients (54%, n = 27) had Grade 4 neck AN [Figure 1]a, Grade 3 neck texture grading (54%, n = 27) [Figure 1]c and grade 4 axilla grading (42%, n = 21) [Figure 1]b and [Table 2].
Figure 1: Acanthosis nigricans grading (a) Acanthosis nigricans neck Grade 4 (b) Acanthosis nigricans Axilla Grade 4 with striae (c) Acanthosis nigricans neck texture Grade 3

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Table 2: Grades of acanthosis nigricans according to acanthosis nigricans site

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Blood sugar and serum insulin

Compared with OB-AN group, OB+AN group had statistically significant higher levels of FBS (P = 0.009), serum insulin-fasting (P = 0.002), serum insulin-postprandial (P = 0.001) and HOMA-IR (P = 0.002). However, the difference of 2 h postprandial blood sugar levels was nonsignificant (P = 0.091) [Table 1].

Acanthosis nigricans, serum adiponectin levels, and body mass index

OB+AN group subjects had statistically significant lower mean levels of serum adiponectin (P = 0.001) [Figure 2] and [Table 1]. Using Spearman's rank correlation between grades (severity) of AN and serum adiponectin levels, statistically significant inverse relationship was found between the two, implying that the presence of AN predicts lower levels of serum adiponectin [Figure 3]a, [Figure 3]b, [Figure 3]c and [Table 3].
Figure 2: Box plot of serum adiponectin levels (μg/ml) in OB+AN and OB-AN subjects. The median, interquartile box and whisker range of the subjects in OB+AN group is smaller than subjects in OB-AN group. There is statistically significant difference between the two groups in terms of serum adiponectin levels. OB+AN - obese subjects with acanthosis nigricans; OB-AN - obese subjects without acanthosis nigricans

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Figure 3: (a) Correlations between serum adiponectin levels and acanthosis nigricans neck grading (b) Correlations between serum adiponectin levels and neck texture grading (c) Correlations between serum adiponectin levels and Acanthosis nigricans axilla grading

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Table 3: Spearman's rank correlation (rho) between grades of acanthosis nigricans and serum adiponectin levels and body mass index

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Grades of AN also had positive relationship with BMI (Spearman's correlation coefficient r = 0.618, P < 0.001 for AN neck grading; r = 0.453, P = 0.001 for AN neck texture grading; r = 0.513, P < 0.001 for AN axilla grading) [Figure 4]b and [Table 3]. It was also found clinically that higher the grade of AN neck and higher the BMI in the individual, more are the chances of presence of AN in sites other than neck such as axilla, antecubital fossa, knuckles, groin and popliteal fossa.
Figure 4: (a) Correlations between Acanthosis nigricans neck grading and Homeostatic model assessment of insulin resistance (HOMA-IR) (b) Correlations between serum adiponectin and body mass index (c) Correlations between serum adiponectin and HOMA-IR

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Acanthosis nigricans and insulin resistance

Mean fasting and postprandial serum insulin levels in OB+AN group was found to be higher than OB-AN group with difference being statistically significant (P < 0.001 for fasting serum insulin levels and P = 0.002 for postprandial insulin levels) [Table 1]. AN grades had direct correlation with HOMA-IR (Spearman's rank coefficient r = 0.678, P < 0.001 for AN neck grades [Figure 4]a; r = 0.506, P < 0.001 for AN texture grading; and r = 0.692, P < 0.001 for AN axilla grading) [Table 3]. According to our study, AN of axilla was most significantly related to hyperinsulinemia. Furthemore, serum adiponectin levels correlated inversely with HOMA-IR (r = −0.736, P ≤ 0.001) [Figure 4]c and [Table 4].
Table 4: Correlation matrix showing Pearson's r and P values for study variables among patients with acanthosis nigricans

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HOMA-IR >2.7 was present in 35 (70%) of the 50 OB+AN group patients and only in 13 (43.3%) out of 30 OB-AN group patients with statistically significant difference (P = 0.002) in HOMA-IR between the two groups. Patients in OB+AN group were 3.05 times (Odd's ratio) more likely to have IR than OB-AN group patients (95% confidence interval 1.19–7.82; P = 0.02). [Table 4] shows the correlation matrix showing Pearson's r and P values for study variables among patients with AN.


  Discussion Top


In this study, we evaluated changes that would be associated with the presence of AN in children and adolescents with OB. OB causes a state of IR, which leads to subsequent hyperinsulinemia. Hyperinsulinemia increases free circulating IGF-1 levels, that act on IGF receptors in epidermis leading to epidermal cell growth and differentiation and subsequently the development of AN.[11]

AN has been shown to be a risk factor for dysglycemia, independent of OB.[12] Our results showed that the obese children with AN had significantly abnormal BMI, blood sugar levels, and serum insulin compared with obese without AN and a highly significant association of AN with IR (HOMA-IR). Fasting serum insulin alone is considered to be a poor surrogate of IR although it may signify compensatory hyperinsulinemia.[13] We used HOMA-IR as a measure to give a physiological estimate of glucose homoeostasis.

Relation between grades of acanthosis nigricans and homeostatic model assessment of insulin resistance

All the 3 calculated grades of AN correlated positively with BMI (P = 0.001) and HOMA-IR (P = 0.001). The correlation coefficient (ρ rho value) of AN had a higher value with HOMA-IR than with BMI, indicating the better correlation of AN severity with HOMA-IR values than with BMI, consistent with the study by Bonet et al.,[14] giving us the idea of the severity of IR in the subjects and allowing its usage as clinical surrogate to assess IR.[15]

Relation between serum adiponectin and acanthosis nigricans

Adiponectin is a key adipokine (protein secreted by adipocytes) that functions as an insulin sensitizer and its reduced levels are emerging marker of metabolic derangement. It can be measured quantitatively in the serum by enzyme-linked immunosorbent assay (ELISA) or by latex particle-enhanced turbidimetric immunoassay (LTIA), a more convenient and faster technique.[16] Our results showed that higher grades (severity) of AN had correlated negatively with serum adiponectin levels [Figure 2] and [Table 4]. This being probably the first study to investigate the correlation of grades of AN with serum adiponectin levels in children. Venkatswami et al. had investigated the same in adults.[17] Also, there were statistically significant lower levels of serum adiponectin in OB+AN group as compared to OB-AN group [Table 1].

Relation between serum adiponectin and insulin resistance

We observed inverse relation of serum adiponectin levels with IR (HOMA-IR) [Figure 4]c. There was also significant inverse relation between serum adiponectin levels and BMI, in concordance with studies done by Aleidi et al. and Yildiz et al.[18],[19]

We also found that mean value of HOMA-IR in OB+AN group was higher than in OB-AN group, as studied by Ng et al., Shalitin et al., and Sayariferd et al., as well. IR also correlated directly with age as in previous studies.[20],[21],[22] Study by Gonzalez-Saldivar G et al. has even proposed knuckle AN as a sole clinical tool to detect IR. It has also been suggested that the physiological IR during puberty also accounts for AN to some extent in this age group.[23] IR and OB are strongly related to Type 2 diabetes mellitus (T2DM).[24] T2DM is now being increasingly diagnosed in adolescent and young adult population. Hence it is also important to control OB right from childhood by adopting active lifestyle, healthy diet, and early control and diagnosis of OB and OB related complications.[25] Recent studies have also shown that raising serum adiponectin levels by various measures can have a promising novel therapeutic role in managing OB related ailments such as MS, T2DM, and coronary artery disease.

Limitations

Small sample size due to lack of resources and time-bound nature of the study. Children and adolescents were inducted into the study on voluntary basis which might have resulted in sampling bias. Normal healthy nonobese controls were not included and we did not follow-up the patients so as to comment on the change in parameters happening in due course of time.


  Conclusions Top


We conclude that AN and its grading can be a very easy-to-use, convenient and simple clinical tool to detect IR in children. Serum adiponectin levels are another lab parameter which correlated negatively with grading of AN and can be used in obese subjects as a marker to confirm IR more research needs to be done with regard to the above parameters to confirm the same.

Declaration of consent

The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s) of the patient. In the form the parent(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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