level increases the risk of acne

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Journal of General - Procedural Dermatology & Venereology Journal of General - Procedural Dermatology & Venereology Indonesia

Indonesia

Volume 3

Number 1 December Edition Article 4

12-31-2018

Elevated homeostatic model assessment of insulin resistance Elevated homeostatic model assessment of insulin resistance level increases the risk of acne

level increases the risk of acne

Stefani Nurhadi

Dermato-Venereology Department, Faculty of Medicine, University Udayana – Sanglah General Hospital, Denpasar, Indonesia

IGAA Praharsini

AAGP Wiraguna

Follow this and additional works at: https://scholarhub.ui.ac.id/jdvi

Part of the Dermatology Commons, Integumentary System Commons, and the Skin and Connective Tissue Diseases Commons

Recommended Citation Recommended Citation

Nurhadi, Stefani; Praharsini, IGAA; and Wiraguna, AAGP (2018) "Elevated homeostatic model assessment of insulin resistance level increases the risk of acne," Journal of General - Procedural Dermatology &

Venereology Indonesia: Vol. 3: No. 1, Article 4.

DOI: 10.19100/jdvi.v3i1.83

Available at: https://scholarhub.ui.ac.id/jdvi/vol3/iss1/4

This Article is brought to you for free and open access by UI Scholars Hub. It has been accepted for inclusion in Journal of General - Procedural Dermatology & Venereology Indonesia by an authorized editor of UI Scholars Hub.

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Original article

Elevated homeostatic model assessment of insulin resistance values increases the risk of acne

Stefani Nurhadi, IGAA Praharsini, AAGP Wiraguna

Email: stefani_nurhadi@hotmail.com

Abstract

Background: Insulin resistance and high carbohydrate diets are currently considered to be influential in acne aetiology. Insulin is a hormone that does not only regulate the concentration of blood glucose but also affects the production of sebum and through the Insulin Growth Factor-1 (IGF-1) receptor stimulates androgen synthesis which will increase the proliferation of keratinocytes duct and the production of sebum in acne of the pilosebaceous.

Methods: This is a cross sectional observational analytic study involving 38 acne patients and 38 controls.

This study aims to determine whether the increase in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) value is a risk factor for acne. HOMA-IR formula was used to determine insulin activity in basal state. High HOMA-IR values are expressed from cut-off point ≥2. Subject was recruited with consecutive sampling who meets inclusion and exclusion criteria. Fasting insulin and blood glucose levels was derived from venous blood examination.

Results: The average age of acne subjects was 23.71 years old in both groups (10 men and 28 women).

The mean value of HOMA-IR in the acne group was higher (2.63 ± 0.29) than those in the control group (1.71

± 0.26) and was statistically significant difference (p value <0.001). The prevalence ratio was 31.58, meaning that patients with high HOMA-IR were 31.6 times more likely to have acne than patients with normal HOMA- IR values. These results were statistically significant (p <0.001).

Conclusion: Elevated HOMA-IR is one of the factors which increase the risk of acne development in an individual.

Keywords: acne, diet, insulin, insulin resistance

Background

Acne vulgaris (AV) is a disorder of the pilosebaceous glands that usually appears on the face, upper body and upper arms.¹ Although AV is a self limiting disease, it has long-term consequences as the formation of permanent scars.² Acne vulgaris and acne scars can also have significant psychosocial effects such as embarrassment, low self-esteem, social isolation, frustration, anxiety, depression and even suicidal ideation.^3-5 Acne vulgaris affects 40-50 million individuals in the United States with peak incidence in adolescents.² According to the study of Indonesian Dermatology Study of Cosmetics, acne prevalence was 60% in 2006, 80% in 2007 and 90% in 2009.⁶ Retrospective studies of AV

prevalence in adult women over the age of 25 years old in the Dermato-Venereology Division Sanglah Denpasar from January 2013 - December 2014, obtained 4.71% of AV cases were due to hormonal imbalance.⁷

Physiologically, acne occurs during puberty and adolescence, when the response to high glycemic load diet increases compared with adults and prepuberty which is caused by decreased insulin sensitivity.⁸ Acne can also be a component of several systemic diseases or syndromes associated with insulin resistance such as seborrhoea, acne, hirsutism and alopecia (SAHA) syndrome, poly cystic ovary syndrome (PCOS) and hyperandrogenism syndrome, insulin resistance and acanthosis nigricans (HAIRAN).⁹ Available

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data support the role of a high glycemic index food diet in influencing hormonal factors which contribute to the AV prevalence and severity.^10-12 Insulin receptors are expressed on epidermal keratinocytes and sebocytes. Hyperinsulinemia may cause proliferation of basal keratinocytes in the pilosebaceous ducts leading to failure of terminal differentiation of the follicular corneocytes and stimulation of the lipogenesis of the sebaceous glands, so insulin plays an active role in the pathogenesis of acne. In addition, insulin can stimulate androgen synthesis, causing high production of sebum known to be associated with the severity of AV.^9,13

Homeostatic Model Assessment Of Insulin Resistance (HOMA-IR) is a formula used to determine the activity of insulin in the basal state.¹⁴ There are several methods to detect insulin sensitivity. Among each methods, the gold standards are euglycemic clamp and modified minimal model however these methods are too invasive hence HOMA-IR is more commonly used as a parameter for clinical study.¹⁵ This study aims to prove the theory that high HOMA-IR values are risk factors for acne vulgaris.

Methods

This was an analytic cross sectional study design.

The study was conducted at the Dermatology- Venereology Outpatient Clinic of Sanglah Hospital Denpasar during July until August 2017. Subject population was all patients aged 12 to 55 years old who visited cosmetic subdivision of Dermatologi- Venereology Outpatient Clinic of Sanglah Hospital Denpasar during the study period.

Inclusion criteria were both new and preexisting acne vulgaris patients from all degree of severity who visited cosmetic subdivision of Dermatology and Venereology Outpatient Clinic of Sanglah Hospital Denpasar during the study period, which met the clinical acne diagnostic criteria; male or female aged 12 to 55 years old. Exclusion criteria were patients receiving isotretinoin treatment, hormonal therapy (such as cyproterone acetate, ethynyl estradiol and drospirenone), drugs affecting insulin metabolism (such as metformin and pioglitazone) or corticosteroids in the past 1 month and have disease/hormonal imbalances such as pregnancy, breastfeeding and ovarian tumors.

Sampling was done using consecutive sampling method. The control group was selected randomly and age-matched. To investigate the activity of insulin in basal state, this study used HOMA-IR formula [fasting insulin level (μU / ml) x fasting glucose (mg / dL) / 405 in plasma]. High HOMA-IR value was defined as ≥2, obtained from the mean HOMA-IR + 2SD of control group. Level of fasting insulin and glucose were derived from venous blood examined by immunochemiluminescent method.

This study has obtained ethical clearance from the Research Ethics Commission of Udayana University Medical Faculty/ Sanglah General Hospital Denpasar. Subjects who met the criteria for sampling had been given an explanation and indicated their willingness to participate in the study and signed the informed consent.

The collected data were checked, coded, processed and analyzed using computer software.

Statistical tests were performed with the Statistical Package for Social Sciences (SPSS) program, version 16.0. Statistical analysis consisted of descriptive statistics used for describing general characteristics and distribution of variables such as gender, age, body mass index (BMI), acne severity according to Lehmann 2002, and HOMA-IR.

Normality test used the Shapiro-wilk test. Paired T test was used as a parametric test. Crosstabulation was used for prevalence ratio. Fisher’s exact test was used for obtaining the significance.

The result can be affected by several factors such as samples, place where the study was conducted, and variables used in the research, as well as the sensitivity of the device used.

Results

The study involved 38 acne vulgaris patients and 38 non-acne patients who met inclusion and exclusion criteria and had been matched by age.

General characteristics of the study sample according to the results of descriptive analysis.

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The distribution of body mass index (BMI) in acne group was divided into underweight, normoweight, overweight and obesity. Most of the patients in acne group and non-acne group were normoweight

(63.2%, 57.9%). In terms of acne severity, most of the patients were in mild and moderate group (57.9%, 39.5%) with history of acne (73.7%), as presented in table 1.

Table 1. Characteristic of Subjects with Acne Vulgaris in Sanglah General Hospital 2017

Characteristics

Groups Acne

n=38 (%)

Non-acne n=38 (%) Age (years)

≤14 15-24 25-34 35-44

≥45 Mean ± SD

4 (10.5) 18 (47.4) 14 (36.8) 2 (5.3)

0 (0) 23.71 ± 7.42

2 (5.3) 23 (60.5) 10 (26.3) 3 (7.9)

0 (0) 24.37 ± 7.31

Total 38 38

Sex Male Female

10 (26.3) 28 (73.7)

10 (26.3) 28 (73.7) Body Mass Index (BMI)*

Underweight (<18.5) Normal weight (18.5-22.9) Overweight (23-24.9) Obese (25-29.9) Extremely obese (≥30) Mean ± SD

8 (21.1) 24 (63.2)

5 (13.2) 1 (2.6)

0 (0) 21.32±3.83

9 (23.7) 22 (57.9)

6 (15.8) 1 (2.6)

0 (0) 21.62±3.99 Acne severity**

Mild Moderate Severe

22 (57.9) 15 (39.5) 1 (2.6)

- Family history of acne

Yes No

28 (73.7) 10 (26.3)

22 (57.9) 16 (42.1) HOMA-IR (value)

Mean ± SD 2.63±0.29 1.71±0.26

* BMI based on World Health Organization (WHO) criteria.

** Acne severity is according to Lehmann 2002.

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The mean HOMA-IR in the acne group and non- acne group were 2.63 ± 0.29 and 1.71 ± 0.26, respectively, as presented in Figure 1. HOMA-IR data was within normal distribution (p>0.05). The comparison of HOMA-IR in acne and non-acne group, performed with paired T test, can be seen in Table 2. This table shows that acne group has mean HOMA-IR of 2.63 ± 0.29 and non-acne group had mean HOMA-IR of 1.71 ± 0.26 (p <0.001. This suggests that there is a statistically significant

difference in HOMA-IR between the acne group compared with non-acne group. The standard value of HOMA-IR uses the cut off point 2 based on the mean HOMA-IR of non-acne group + 2SD.

A normal HOMA-IR value is <2. Table 3 shows the high HOMA-IR value was found in 37 subjects in the acne group (97.4%) and 4 subjects in the non- acne group (10.5%). Risk factor calculation from prevalence ratio obtained the value of 31.58. This result was statistically significant with p<0.001.

Figure 1. HOMA-IR Box Plot of Acne and Non-acne Groups

Table 2. Comparison of HOMA-IR Values between Acne and Non-acne patients in Sanglah General Hospital 2017

Mean ± SD Difference ± SD CI 95% P value HOMA-IR Acne (n=38)

HOMA-IR Non-Acne (n=38)

2.63±0,29 1.71±0,26

0.92±0.33 0.81-1.02 <0.001 p significant if p <0.05

Table 3. High HOMA-IR Values as Risk Factors for Acne patients in Sanglah General Hospital 2017

Variable

Groups

Prevalence ratio

CI 95% P value Acne

n=38 (%)

Non-acne n=38 (%) HOMA-IR

High (≥2) Normal (<2)

37(97.4) 1(2.6)

4(10.5) 34(89.5)

31.58 4.565-

218.563

<0.001

p value is considered significant if p <0.05

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Discussion

In this study, the highest number of acne events within the 15-24 year age group was 18 subjects (47.4%) and none was older than 45 years old as shown in Table 5.1. This result corresponds with previous study by Ayudianti and Mizwar et al.^16,17 Acne can occur at various age, but its prevalence peaks during the mid to late adolescence.³

The mean age of acne subjects on this study was 23.71 years old with 13 years old as the youngest and 44 years old as the oldest. Acne often begins during puberty. The highest prevalence of acne is usually during mid to the end of second decade, with more than 85% of teenagers affected and is usually followed by a climbdown in percentage.³ This is apparently caused by adrenal androgen/

dehydroepiandrosterone sulfate (DHEAS) influence which is thought to act as a sebaceous gland activity regulator through its conversion to testosterone and dehydrotestosterone (DHT) at sebaceous gland. DHEAS level is high in newborns, very low in children aged 2-4 years old and starts to increase together with the sebum secretion during puberty. DHEAS level is decreased in both sexes from early adulthood which then persists during the whole lifetime. The regression of DHEAS level is followed by the decline of sebum secretion which explains the low incidence of acne in geriatric population.^(nel) Adolescent acne is thought to be related to the increased anabolic effect of insulin and GH during rapid somatic growth throughout adulthood.^18,19 In this study, it was found that the frequency of acne vulgaris was higher in females, which comprised of 28 patients (73.7%). This data corresponds to a previous study conducted by Pratiwi and Sutanto.^20,21 The domination of female is thought to be caused by hormonal factors.

Sebum is synthesized continually by sebaceous gland and regulated hormonally. Hormon will still influence sebaceous gland activity until adulthood.

In female, a sudden increase in luteinizing hormone (LH) following ovulation triggers increased sebaceous activity.²²

There was no statistically significant difference in BMI between acne group (21.32±3.83) and non- acne group (21.32±3.99). There are several controversial data reporting the effect of BMI on acne development. A study by Lu et al. found that mean BMI in acne subject were significantly higher compared to non-acne subject.²³ However, study by Yang et al. reported otherwise.²⁴Mechanisms that may link the high BMI with acne are thought to be high in androgen serum found in subjects with

obesity. Female patient with acne and obesity have high serum testosterone levels and low sex hormone binding globulin (SHBG) compared with women without obesity which is associated with increased sebum production and acne development. But on the other hand, Increased adipose tissue in obese patients is associated with increased aromatase enzymes. Aromatase is an enzyme converting testosterone to estradiol, which can be found in the sebaceous glands and may play a role in reducing excess androgens.²⁵ In this research, the most acne severity was mild acne in 22 subjects (57.9%), followed by moderate acne in 15 subjects (39.5%) and severe acne in 1 subject (2.6%). This result corresponds to the previous research conducted by Sutanto²¹and Shen et al.²⁶ Because the majority of acne lesions appear on the face, cosmetic and psychological problems are the issue that affect the subjects to seek medication. This is probably why mild acne dominated the subjects profile in this study.

In this research, the authors found 28 acne patients (73.7%) with the family history of acne and 10 patients (26.3%) without it. This is in accordance with the study of twins, 81% of acne was found to be caused by genetic factor compared to 19%

caused by environmental factors.³

HOMA-IR index was used in this study to evaluate insulin resistance. This index has been used to measure insulin resistance since its original publication by Matthews and colleagues in 1985.

There are several methods to detect insulin sensitivity. Among each methods, the gold standards are euglycemic clamp and modified minimal model however, these methods are too invasive hence HOMA-IR is more commonly used as a parameter for clinical study.¹⁵

The HOMA-IR score on acne were higher compared to non-acne group and they were statistically significant. This difference can be seen through the mean result of HOMA-IR on acne group which was higher (2.63+0.29) than that in non-acne group (1.71+0.26) (p<0.001). It can be concluded that there was a statistically significant difference between the two HOMA-IR values in both groups, where the acne group was higher.

A study conducted by Emiroglu et al. in 243 acne patients, it was found that the HOMA-IR value was significantly higher than that in 156 control patients (p<0.001).¹⁵ In a study by Del Prete et al. which compared 22 male subjects with acne and 22 control subjects which age and sex-matched, it was found that acne patients had higher HOMA-IR

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value compared to control (p=0.016).²⁷ A study by Maffeis which compared 7 acne patients and control reported higher HOMA-IR value in acne patients (p=0.05). These higher HOMA-IR value in acne patients can be caused by hyperinsulinemia secondary to high glycemic index diet or several systemic diseases or syndromes related to insulin resistance (PCOS, SAHA, HAIRAN).^9,15

High HOMA-IR value uses the cut off point of 2 based on mean HOMA-IR + 2SD in the non-acne group. HOMA-IR is considered high if it is > 2 and normal if it is < 2. Risk factor calculation from prevalence ratio obtained the value of 31.58, which means patients with high HOMA-IR have 31.6 times higher risk to obtain acne compared to patients with normal HOMA-IR value. This result was statistically significant (p<0.001).

Emiroglu and colleagues conducted an insulin resistance study in acne patients and reported a significantly higher HOMA-IR value in acne group (2.87+2.56) compared to non-acne group (1.63+0.65) (p<0.001) which showed that insulin resistance can affect acne pathogenesis.¹⁵ Another study by Del Prete et al. showed that significant HOMA-IR value increase in acne patients compared to non-acne patients.²⁸

Acne vulgaris is a chronic inflammatory disease of the pilosebaceous unit with multifactorial cause.^3,27 Diet has long been considered less important, however, insulin resistance and carbohydrate diet have been lately considered to be influential in acne etiology. In several studies about acne and diet, low glycemic index food was reported to improve acne vulgaris and insulin resistance.^11,27 The role of insulin resistance has been clearly established in female patients with polycycstic ovarian syndrome (PCOS) with acne vulgaris.^8,28 High glycemic index diet will increase blood glucose which can stimulate insulin secretion which will then increase the HOMA-IR.²⁷

The increased HOMA-IR is thought to be caused by the decreased sensitivity of insulin. Evidence shows that high glycemic food consumption triggers acne by inducing compensatory hyperinsulinemia.²⁹ Prolonged high glycemic index foods consumption will increase blood glucose and insulin level.¹¹ Prolonged high blood glucose can lower the responsiveness of β-cells to glucose stimulation and causes hyperglycemia and increases blood insulin level, which affects androgen and IGF-1 levels, leading to uncontrolled tissue growth and increased androgen synthesis which worsen acne.²⁹

High insulin concentration can exacerbate acne by increasing basal keratinocyte proliferation inside pilosebaceous unit duct leading to failed terminal differentiation of follicular korneocyte. Insulin also stimulates adrenal and gonadal androgen synthesis, androgen receptor signal transduction, sebocyte proliferation, sebum production, and sebaceous gland lipogenesis, which affect acne development.⁹

Insulin reactivity can only occur by inter-receptor signal through IGF-1 receptor. IGF-1 receptor activation is capable of increasing 5α reductase, adrenal dan gonadal androgen synthesis, androgen receptor signal transduction, sebocyte proliferation, and sebum and lipogenesis production. IGF-1 stimulates lipogenesis through sterol regulatory element-binding transcription factor (SREBP)-1 protein induction which regulates fatty acid synthesis.^9,13

IGF-1 increases adrenal sensitivity towards adrenocorticotropic hormone (ACTH) and induces the expression and effectivity of key enzymes for adrenal androgen biosynthesis such as DHEAS.

IGF system also plays an important role in ovarial androgen synthesis. IGF-1 increases LH efficacy on interstitial theca cell thus increases androgen production. IGF-1 and LH stimulate the proliferation of Leydig cell precursor proliferation and are both important local mediators for deoxyribonucleic acid (DNA) synthesis in testis and steroidogenesis.¹³

IGF-1 causes peripheral androgenism through forkhead box protein (FoxO1) phosphorylation.

IGF-1 induces androgen receptor trans-activation.

IGF-1 stimulates FoxO1 thus it leaves AR and moves from nucleus to cytoplasm. With this cytoplasm, IGF-1 signal decreases the androgen receptor suppression so that androgen receptor can function.³⁰

Androgen plays an important role in increasing the size of the sebaceous glands and stimulates sebum production and keratinocyte proliferation in the seboglandularis and akroinfundibulum ducts.

The androgen excess state is associated with increased sebum production and acne severity.

Acne-prone skin shows higher density of the androgen receptor and higher 5α reductase activity than the uninvolved skin. In contrast, anti-androgen decreases sebaceous lipid synthesis and improves acne, where insensitive subjects, lacking functional androgen receptors do not produce sebum and do not develop acne. Thus, hyperinsulinemia promotes acne either directly in the proliferation of

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basal keratinocytes or through their androgenic stimulation of adrenal, testicular and ovarian.³⁰ In this study, HOMA-IR values in acne patients were significantly higher compared with non-acne patients. Considering the cause of acne is multifactorial so the high HOMA-IR value is one of the risk factor for acne development.

The limitation of this study is no examination on the subject's diet so that the high HOMA-IR obtained in the acne group is not necessarily due to the consumption of foods with high glycemic load. For future researchers it is expected to examine diet and its association with increased HOMA-IR and the occurrence of acne.

Conclusion

Based on the results and discussion, it is proven that HOMA-IR value in acne patients is higher than non-acne patients and high HOMA-IR is a risk factor for acne. High HOMA-IR values in acne patients, indicate the factors leading to an increase in fasting blood glucose and insulin, which can be caused by high glycemic load diet. Further research can be conducted on the effect of diet and exercise on HOMA-IR in acne patients. Treatment of acne patients with high HOMA-IR values may be provided with information and education counseling regarding diet and exercise.

Acknowledgements

We would like to recognize our mentors Made Swastika Adiguna, MD., Made Wardhana, MD., and Luh Made Mas Rusyati, MD for sharing their pearls of wisdom with us during the course of this research.

References

1. James WD, Berger TG, Elston DM. Acne. In:

Andrews’ Diseases of the Skin Clinical Dermatology. United Kingdom: Elsevier. 2011.

p. 231-250.

2. Zaenglein AL, Graber EM, Thiboutot DM. Acne vulgaris and acneiform eruptions. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffel DJ, Wolf K, editors. Fitzpatrick’s Dermatology in General Medicine. 8th Ed. New York: McGraw- Hill. 2012.p. 897-917.

3. Zaenglein AL, Thiboutot DM. Acne Vulgaris. In:

Bolognia JL, Jorizzo JL, Schaffer JV.

Dermatology 3^rd Ed. United States: Elsevier Saunders. 2009.p.545-560.

4. Rivera AE. Acne scarring: A review and current treatment modalities. J Am Acad Dermatol.

2008; 59:659-76.

5. Miteva M, Romanelli P. Hypertrophic and keloidal scars. In: Tosti A, Padova MPD, Beer KR, editors. Acne Scar Classification and treatment. London: Informa. 2010.p. 11-19.

6. Tjekyan RM. Acne vulgaris prevalence and risk factors. Jurnal media medika indonesiana.

2008;43(1):6-12 (in Indonesian).

7. Maharani MKD. Profile of acne vulgaris in adult female at dermatovenereology department sanglah general hospital January 1^st 2013- December 31^st 2014. ISDV Annual Scientific Meeting. 2015. Balikpapan (in Indonesian) 8. Maffeis L. Correlation between insulin

resistance and treatment resistance acne (thesis). Bologna: Scienze Dermatologiche – Universita di Bologna. 2013;1-31.

9. Napolitano M, Megna M, Monfrecola G. Insulin resistance and skin diseases. Scientific World Journal. 2015.p.1-11.

10. Dougan P, Rafikhah N. Dark and white chocolate consumption and acne vulgaris: A case control study. Asian Journal of Clinical Nutrition. 2014; 6(2):35-40.

11. Tayel DI, Abdelsalam OM, Elgarem YF, Ali AE.

Dietary intervention to alleviate acne severity.

AJRC journal. 2013;1(5):65-79.

12. Youssef EMK, Youssef MKE. Diet and acne in Upper Egypt. American Journal of Dermatology and Venereology. 2014;3(1):13-22.

13. Melnik BC, Schmitz G. role of insulin, insulin- like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris. Experimental Dermatology.

2009;18:833-841.

14. Lestari WAA. Insulin resistance: Definition, mechanism and laboratory workup. in: Clinical pathology update on SURAMADE 1. Surabaya 13-15 Juli. 2011.1-2 (in Indonesian)

15. Emiroglu N, Cengiz FP, Kemeriz F. Insulin resistance in severe acne vulgaris. Postep Derm Alergol. 2015;32(4):281-285.

16. Ayudianti P. Retrospective study: Factors that induce acne. BIKKK. 2014;26(1):41-47 (In Indonesian)

17. Mizwar M, Kapantow MG, Suling PL. Acne vulgaris profile at Prof. dr. D. Kandou year 2009-2011. ECL. 2013; 1(2):1-7. (in Indonesian)

18. Kurtoglu S, Hatipoglu N, Masicioglu M, Kendirci M, Keskin M, Kondolot M. Insulin resistance in obese children and adolescents: HOMA-IR cut- off levels in the prepubertal and pubertal periods. J clin res ped endo. 2010; 2(3):100- 106.

(9)

19. Shih SR, Tseng CH. The effects of aging on glucose metabolism. Taiwan geriatrics &

gerontology. 2009;4(1):27-38.

20. Pratiwi RE. Characteristics of acne vulgaris patients in Dermatovenereology Clinic Sakura Derma Bandung (thesis). 2016. Bandung:

Universitas Maranatha (in Indonesian).

21. Sutanto R. Acne severity in relation to MDA levels (thesis). 2013. Denpasar: Universitas Udayana in Indonesian).

22. Baumann L, Keri J. Acne (Type 1 sensitive skin). In: Baumann, L. Cosmetic Dermatology.

2^nd Ed. New York: McGraw-Hill. 2009. P. 121- 127.

23. Lu LY, Lai HY, Pan ZP, Wu ZY, Chen WC, Ju Q. Obese/overweight and the risk of acne vulgaris in Chinese adolescents and young adults. Hong Kong J. Dermatol. Venereol.

2017;25: 5-12.

24. Yang JH, Weng SL, Lee CY. A comparative study of cutaneous manifestations of hyperandrogenism in obese and non obese Taiwanese women. Arch Gynecol Obstet.

2010;282:327-333.

25. Dessinioti C, Zouboulis CC. Body Mass Index.

In: Zouboulis, C.C., Katsambas, A.D., Kligman, A.M. Pathogenesis and treatment acne and rosacea. London: Springer.

2014.p.295-297.

26. Shen Y, Wang T, Zhou C, et al.

Prevalence of acne vulgaris in Chinese adolescents and adults: a community-based study of 17,345 subjects in six cities. Acta Derm Venereol. 2012;92:40-44.

27. Arora MK, Yadav A, Saini V. Role of hormones in acne vulgaris. J clin biochem.

2011;44:1035-1040.

28. Del Prete M, Mauriello MC, Faggiano A, Di Somma C, Monfrecola G, Fabbrocini G, Colao A. Insulin resistance and acne: A new risk factor for men? Endocrine. 2012;42:555-560.

29. Lakshmi C. Hormonal therapy in acne. Indian J Dermatol Venereol Leprol. 2013;79(3):322- 337.

30. Kumari R, Thappa DM. Role of insulin resistance and diet in acne. Indian J Dermatol Venereol Leprol. 2013;79:291-299.