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Original Article

Assessment of Patients with Periorbital Melanosis for Hyperinsulinemia and Insulin Resistance

Thappa, Devinder M.; Chandrashekar, Laxmisha; Rajappa, Medha1; Usha, R.; Muthupandi, K.1; Mohanraj, Palani S.1; Munisamy, Malathi; Singh, Nidhi

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Indian Dermatology Online Journal: Mar–Apr 2021 - Volume 12 - Issue 2 - p 244-249
doi: 10.4103/idoj.IDOJ_491_20
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Skin is a major organ system that serves as a window to the changes that happen inside our body and its disorders can sometimes act as a marker for the identification of the underlying disease.[1] Periorbital melanosis (PM) is common dermatological condition that can affect patients of any age and gender. PM is characterized by bilateral hyperpigmentation of the periorbital region that is darker in comparison with the adjoining skin. It is also known by various names such as dark circles, periorbital hyperpigmentation, infraorbital hyperpigmentation, periorbital pigmentation.[2] It is a benign condition with enigmatic pathogenesis. PM can be further divided into two clinical types based on etiology. The first type also known as primary PM manifests as bilateral darkening of the periorbital skin that is not associated with any systemic or local diseases. It is also known as idiopathic cutaneous hyperchromia of the orbital region.

The second type is hyperpigmentation associated with a known cause of systemic or local disease. This condition also worsens with physiological changes associated with aging such as sagging of skin and abnormal lipid deposits around the orbital region.[3] The etiology of PM is multifactorial that include familial, physiological, or associated with chronic illnesses.[4] Various factors that can cause PM includes periorbital melasma, fixed drug eruptions, periorbital acanthosis nigricans, atopy, allergic contact dermatitis, dermal melanocytosis, post-inflammatory hyperpigmentation, shadowing effect due to laxity of periorbital skin and aging. Other environmental causes that can cause PM includes smoking, alcohol, lack of sleep, and stress.[5]

Many cutaneous disorders have been identified as a marker of insulin resistance (IR) that includes acanthosis nigricans, skin tags, hirsutism, and acne.[67] IR is characterized by the subnormal response in the uptake of glucose by target organs to normal insulin levels and associated with hyperinsulinemia. Hyperinsulinemia can lead to several metabolic consequences such as decrease in levels of sex hormone binding globulin, increase in insulin like growth factor-1 (IGF-1), also causes elevation in levels of leptin, androgen, and insulin like growth factor binding protein 3 (IGFBP-3). These hormones play an active role in the regulation of gene expression required for the proliferation of skin cells which in turn may result in skin manifestations such as acanthosis nigricans and epithelial cell carcinomas.[67]

Leptin and adiponectin are protein hormones synthesized mainly from adipocytes. Leptin inhibits hunger by acting on the arcuate nucleus of the brain.[8] In obese patients, there is a decreased sensitivity to leptin, leading to hyperleptinemia which is a marker of metabolic syndrome.[9] Adiponectin, on the other hand, is inversely correlated with obesity and metabolic syndrome.[10] Leptin and adiponectin have opposite actions on inflammation and IR. Leptin increases IR by its pro-inflammatory action, whereas adiponectin has anti-inflammatory properties which can downregulate the pro-inflammatory cytokines.[11] Recently increased leptin: adiponectin ratio (L/A ratio) is also increasingly being used to assess IR among patients with type 2 DM.[121314]

Some markers such as acanthosis nigricans have been reliable and consistent with the euglycemic clamp test, the gold standard for measurement of IR.[1516] These cutaneous markers offer several advantages like easy identification, non-invasive, and less time consuming compared to traditional indices for measurement of IR such as Homeostatic Model Assessment (HOMA-IR). A recent study has found that PM is associated with chronic illness such as atopy, anemia, irregular menses, and other post-inflammatory pigmentation disorders including acanthosis nigricans.[4]

There is a possible connection between hyperinsulinemia, associated with IR and PM. Identification of such markers may help general practitioners, family physicians, and dermatologists with a valuable tool in early diagnosis and timely intervention for prevention and management of type 2 diabetes mellitus. There is a lacuna in the literature regarding the association of this extremely common aesthetic condition with IR. Hence, in this study, we evaluated the patients with PM in people above 35 years of age for associated IR and metabolic complications.

Materials and Methods


This was a cross-sectional study conducted in our hospital, a tertiary care center in South India. This study was done after getting approval from the Institute Ethics Committee (Human studies) (JIP/IEC/2014/1/241).

Study population

Informed consent was obtained from the study participants, before enrollment into this study. Since no previous data was available regarding the problem under investigation, a convenient sample of 100 was taken in each group. Consecutive patients with PM, (aged between 35 and 60 years) attending the Dermatology Clinic of our hospital, were recruited as cases. Age- and gender-matched healthy volunteers without periorbital pigmentation were recruited as controls. The participants were examined by a dermatologist, who verified the diagnosis of PM based on bilateral round or semi-circular homogeneous brown or dark brown pigmentation in the periocular region of the face. Other cutaneous markers of IR were also recorded. Individuals with familial pigmentation, atopy (urticaria, asthma, allergic conjunctivitis, and rhinitis), post-inflammatory pigmentation, erythema dyschromicum perstans, positive shadow effect, dermal melanocytosis, diagnosed/established cases of cardiovascular disease, and morbid obesity-BMI >30 kg/m2 were excluded from the study.

Assessment of clinical parameters

The clinical characteristics were recorded using standard questionnaire in a predetermined proforma. Age, gender, height, weight, body mass index (BMI), waist circumference, blood pressure, and disease duration were recorded in study subjects.

Grading of PM was done in comparison to surrounding skin as follows: 0 – skin colour comparable to other facial skin areas, 1 – faint pigmentation of infraorbital fold, 2 – pigmentation more pronounced, 3 – deep dark colour, all four lids involved, 4 – grade 3 + pigmentation spreading beyond infraorbital fold.

Assessment of biochemical parameters

Five (5) ml of blood was collected from all study participants, in fasting state. Fasting glucose and lipid profile were estimated using fully automated clinical chemistry analyzer. Fasting insulin, leptin, adiponectin and IGF-1 levels were assayed in serum using commercially available ELISA kits. HOMA-IR formula was used to calculate IR by using fasting insulin and fasting glucose. Leptin: adiponectin ratio was calculated from serum leptin and serum adiponectin levels.

Statistical analysis

All categorical variables were presented as frequencies and percentages. The normality of the continuous data was tested using the Kolmogorov–Smirnov test. Normally distributed data were presented as mean with SD (Standard Deviation) and median with inter-quartile range was used to present the non-Gaussian data. Student t-test was used to assess the difference in continuous variables between the two groups. Association between continuous variables was studied by Pearson correlation. All statistical analysis was carried out using SPSS version 20 at 5% level of significance and P value of <0.05 was considered as significant.


One hundred (100) patients with periorbital melanosis and 100 age and gender-matched healthy controls without periorbital melanosis were included in this study. The baseline characteristics are depicted in Table 1. The mean (with SD) duration of disease in patients with periorbital melanosis was 39.75 (± 42.96) months. Among the cases, 31 patients had pigmentation that extended beyond the periorbital region. The clinical characteristics of the cases were given in Table 2. In comparison with healthy controls, the prevalence of some of the risk factors such as photosensitivity, cosmetic usage, pigmentation elsewhere in the body, history of refractive error, sleep deprivation, constant eye rubbing, smoking, alcoholism, and chronic stress were higher in patients with PM [Table 3].

Table 1:
Comparison of baseline parameters between cases and controls
Table 2:
Disease characteristics in patients with periorbital melanosis
Table 3:
Comparison of risk factors associated with periorbital melanosis between cases and controls

Figure 1a-g shows the comparison of the study parameters between the patients with PM and controls. The serum leptin levels were significantly higher in patients with PM compared to healthy controls. The serum levels of adiponectin were significantly lower in cases as compared to controls. Hence, leptin adiponectin ratio (L/A ratio) was also higher in cases as compared to controls. The serum levels of fasting glucose, insulin and IR, as calculated by HOMA-IR were significantly higher in patients with periorbital melanosis, compared with controls. There was no significant change in the serum levels of IGF-1 between cases and healthy controls [Figure 1a-g]. On multivariate regression analysis, leptin, adiponectin, and HOMA-IR were found to be significant, even after adjusting for BMI, blood pressure, LDL and HDL cholesterol.

Figure 1:
Plasma levels of leptin (a), adiponectin (b), L/A ratio (c), insulin (d), glucose (e), IGF-1 (f), HOMA-IR (g) in patients with periorbital hyperpigmentation (cases) and healthy volunteers (controls). ***P < 0.001


PM is a common dermatologic condition, although easily diagnosed, cure is not easy.[17] PM is known by various synonyms, and has varied multifactorial etiology. Factors promoting its occurrence can be exogenous as well as endogenous, ranging from ageing lax skin, periorbital oedema, dermal melanocytosis, post-inflammatory hyperpigmentation to periorbital acanthosis nigricans. An Indian study has shown that among Indians, the most common cause of PM is constitutional (51.5%) followed by post-inflammatory (22.5%) and vascular (8%).[2] On the other hand, term facial acanthosis nigricans (FAN) is given to brown to black macular pigmentation with blurred margins, commonly found on the forehead, temporal region, zygomatic, and malar areas with varying degrees of textural changes ranging from mild roughness to frank verrucous appearance of the affected areas of the face.[18] Increased prevalence of obesity, metabolic syndrome, and IR has been documented in such cases.[1819] Apart from face, acanthosis nigricans has been documented over the neck, axilla, groin, and acral regions in most of these cases. Verma et al.[18] also observed periorbital darkening in 17.6% of their FAN cases, however Panda et al.[19] noted in 14.6% of cases of FAN. In our study, PM cases without morbid obesity in the age group of 35–60 years were compared with age- and sex-matched controls to look for any association with circulating adipokines and IR to periorbital melanosis.

Periorbital melanosis is one of the most common dermatological condition, whose usefulness as a cutaneous marker remains unexplored till today. Therefore, in the present study, we compared the patients with periorbital melanosis and healthy controls on various parameters related to IR. We found higher levels of leptin, L/A ratio in patients with PM as compared to controls. We also found lower levels of adiponectin in cases as compared to healthy controls. Leptin and adiponectin are two major adipocytokines that play a key role in the regulation of metabolic disorders such as obesity and diabetes mellitus.[20] Leptin plays an important role in the regulation of body weight.[9] Previous studies have shown that higher levels of leptin in obese patients, suggesting resistance to its action by its receptors in the target organs.[1121] Earlier studies have shown that higher levels of leptin were associated with both BMI and IR.[222324] Leptin is a pro-inflammatory cytokine with a role in immune response. It induces the production of IL-6, which in turn induces C-reactive protein (CRP) production in the liver.[25] On the other hand, adiponectin was shown to have anti-inflammatory and antidiabetic properties.[26] It was also shown to have a negative correlation with obesity.[27] PM was also reported to be a pro-inflammatory condition and it was shown to have been associated with post-inflammatory causes such as atopic dermatitis and allergic contact dermatitis.[2] Hence our observation is consistent with this hypothesis that PM, being a pro-inflammatory condition would be associated with elevated L/A ratio. In some studies, it has been found in association with FAN.[1819]

In this study, the levels of fasting insulin, fasting glucose, and IR as calculated by HOMA-IR was higher in patients with PM as compared to healthy controls. There is no significant difference in the levels of IGF-1 in cases as compared to controls. IR occurs due to increased adipocytes, which secretes several cytokines such as leptin, resistin, TNF-α, IL-6, IL-18, all of which are implicated in the development of metabolic syndrome.[28] It has been reported that hyperglycemia, which is seen in the majority of the patients with IR, develops only at a later stage due to compensatory hyperinsulinemia.[29] Therefore, IR can be regarded as an early subclinical stage in the development of impaired glucose tolerance and diabetes. Identification of patients with IR before the development of clinical signs such as glucose intolerance will provide a potential for early intervention and prevention of diabetes and metabolic syndrome. IR has been shown to have an association with several cutaneous markers in the literature.[16] Previous studies also reported that IR is associated with dermatological disorders such as psoriasis and vitiligo.[1] The most plausible explanation for association of IR with dermatological lesions is that hyperinsulinemia causes increased levels of IGF-1 in keratinocytes and increases their proliferation.[3031] Our findings also show a significant elevation in fasting glucose, fasting insulin, and HOMA-IR consistent with past observations. But our results failed to show any significant change in the levels of IGF-1 between the PM group and controls. This could be due to the various mechanisms underlying the pathogenesis of periorbital melanosis other than IGF-1, which needs to be further explored.

This study had a few limitations. Though age- and sex-matched controls were taken, but certain variables were distinctly more in case group versus controls. Although there is an association of periorbital melanosis with IR, the etiopathogenesis of PM remains unclear. Further research in this area is required to establish the molecular mechanisms underlying the development of periorbital melanosis and its usefulness as a cutaneous marker for IR.


Our observations indicate that patients with periorbital melanosis have significantly higher levels of leptin, fasting glucose, fasting insulin, L/A ratio and HOMA-IR and lower levels of adiponectin when compared to age and gender-matched controls. PM as a marker of IR in adults (35–60 years) may help in identifying patients early and thus aid in the early prevention and management of the disease.

Financial support and sponsorship

This research was funded by IADVL-L'Oreal Hair and Skin Research Grant. Funding from Indian Association of Dermatologists, Venereologists, and Leprologists in the name of Dr. Devinder Mohan Thappa is gratefully acknowledged.

Conflicts of interest

There are no conflicts of interest.


The authors wish to acknowledge the study participants, without whose support this study would not have been possible.


1. Napolitano M, Megna M, Monfrecola G. Insulin resistance and skin diseases ScientificWorldJournal. 2015. 2015 doi: 10.1155/2015/479354
2. Sheth PB, Shah HA, Dave JN. Periorbital hyperpigmentation: A study of its prevalence, common causative factors and its association with personal habits and other disorders Indian J Dermatol. 2014;59:151–7
3. Verschoore M, Gupta S, Sharma VK, Ortonne JP. Determination of melanin and haemoglobin in the skin of idiopathic cutaneous hyperchromia of the orbital region (ICHOR): A study of indian patients J Cutan Aesthet Surg. 2012;5:176–82
4. Sarkar R, Das A. Periorbital hyperpigmentation: What lies beneath? Indian Dermatol Online J. 2018;9:229–30
5. Roh MR, Chung KY. Infraorbital dark circles: Definition, causes, and treatment options Dermatol Surg. 2009;35:1163–71
6. El Safoury OS, Shaker OG, Fawzy MM. Skin tags and acanthosis nigricans in patients with hepatitis C infection in relation to insulin resistance and insulin like growth factor-1 levels Indian J Dermatol. 2012;57:102–6
7. Patidar PP, Ramachandra P, Philip R, Saran S, Agarwal P, Gutch M, et al Correlation of acanthosis nigricans with insulin resistance, anthropometric, and other metabolic parameters in diabetic Indians Indian J Endocrinol Metab. 2012;16(Suppl 2):S436–7
8. Brennan AM, Mantzoros CS. Drug insight: The role of leptin in human physiology and pathophysiology emerging clinical applications Nat Clin Pract Endocrinol Metab. 2006;2:318–27
9. Pan H, Guo J, Su Z. Advances in understanding the interrelations between leptin resistance and obesity Physiol Behav. 2014;130:157–69
10. Ukkola O, Santaniemi M. Adiponectin: A link between excess adiposity and associated comorbidities? J Mol Med (Berl). 2002;80:696–702
11. Lopez-Jaramillo P, Gomez-Arbelaez D, Lopez-Lopez J, Lopez-Lopez C, Martinez-Ortega J, Gomez-Rodriguez A, et al The role of leptin/adiponectin ratio in metabolic syndrome and diabetes Horm Mol Biol Clin Investig. 2014;18:37–45
12. Inoue M, Maehata E, Yano M, Taniyama M, Suzuki S. Correlation between the adiponectin-leptin ratio and parameters of insulin resistance in patients with type 2 diabetes Metabolism. 2005;54:281–6
13. Kotani K, Sakane N, Saiga K, Kurozawa Y. Leptin: Adiponectin ratio as an atherosclerotic index in patients with type 2 diabetes: Relationship of the index to carotid intima-media thickness Diabetologia. 2005;48:2684–6
14. Satoh N, Naruse M, Usui T, Tagami T, Suganami T, Yamada K, et al Leptin-to-adiponectin ratio as a potential atherogenic index in obese type 2 diabetic patients Diabetes Care. 2004;27:2488–90
15. Crook M. Skin tags: A useful clinical sign for insulin resistance? Eur J Dermatol. 2012;22:5–6
16. Gonzalez-Saldivar G, Rodriguez-Gutierrez R, Ocampo-Candiani J, Gonzalez-Gonzalez JG, Gomez-Flores M. Skin manifestations of insulin resistance: From a biochemical stance to a clinical diagnosis and management Dermatol Ther (Heidelb). 2017;7:37–51
17. Daroach M, Kumaran MS. Periorbital hyperpigmentation − An overview of the enigmatous condition Pigment Int. 2018;5:1–3
18. Verma S, Vasani R, Joshi R, Phiske M, Punjabi P, Toprani T, et al A descriptive study of facial acanthosis nigricans and its association with body mass index, waist circumference and insulin resistance using HOMA2 IR Indian Dermatol Online J. 2016;7:498–503
19. Panda S, Das A, Lahiri K, Chatterjee M, Padhi T, Rathi S, et al Facial acanthosis nigricans: A morphological marker of metabolic syndrome Indian J Dermatol. 2017;62:591–7
20. Gupta V, Mishra S, Mishra S, Kumar S, Gupta V. Association of Leptin: Adiponectin ratio and metabolic risk markers in postmenopausal women Immunol Lett. 2018;196:63–7
21. Stefanovic A, Kotur-Stevuljevic J, Spasic S, Bogavac-Stanojevic N, Bujisic N. The influence of obesity on the oxidative stress status and the concentration of leptin in type 2 diabetes mellitus patients Diabetes Res Clin Pract. 2008;79:156–63
22. Abdella NA, Mojiminiyi OA, Moussa MA, Zaki M, Al Mohammedi H, Al Ozairi ES, et al Plasma leptin concentration in patients with Type 2 diabetes: Relationship to cardiovascular disease risk factors and insulin resistance Diabet Med. 2005;22:278–85
23. Uslu S, Kebapci N, Kara M, Bal C. Relationship between adipocytokines and cardiovascular risk factors in patients with type 2 diabetes mellitus Exp Ther Med. 2012;4:113–20
24. Asakawa H, Tokunaga K, Kawakami F. Relationship of leptin level with metabolic disorders and hypertension in Japanese type 2 diabetes mellitus patients J Diabetes Complications. 2001;15:57–62
25. Wannamethee SG, Tchernova J, Whincup P, Lowe GD, Kelly A, Rumley A, et al Plasma leptin: Associations with metabolic, inflammatory and haemostatic risk factors for cardiovascular disease Atherosclerosis. 2007;191:418–26
26. Spranger J, Kroke A, Mohlig M, Bergmann MM, Ristow M, Boeing H, et al Adiponectin and protection against type 2 diabetes mellitus Lancet. 2003;361:226–8
27. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.1999 Biochem Biophys Res Commun. 2012;425:560–4
28. Jung UJ, Choi MS. Obesity and its metabolic complications: The role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease Int J Mol Sci. 2014;15:6184–223
29. Kahana M, Grossman E, Feinstein A, Ronnen M, Cohen M, Millet MS. Skin tags: A cutaneous marker for diabetes mellitus Acta Derm Venereol. 1987;67:175–7
30. Barbato MT, Criado PR, Silva AK, Averbeck E, Guerine MB, Sa NB. Association of acanthosis nigricans and skin tags with insulin resistance An Bras Dermatol. 2012;87:97–104
31. Cordain L, Eades MR, Eades MD. Hyperinsulinemic diseases of civilization: More than just Syndrome X Comp Biochem Physiol A Mol Integr Physiol. 2003;136:95–112

Adipokines; adiponectin; insulin like growth factor-1; insulin resistance; leptin; periobital hyperpigmentation

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