Report
Insulin resistance in patients with post-adolescent acne Ilknur Balta1, MD, Ozlem Ekiz2, MD, Pınar Ozuguz3, MD, Ihsan Ustun4, MD, Semsettin Karaca3, MD, Seval Dogruk Kacar3, MD, and Meral Eksioglu5, MD
1 Department of Dermatology, Kecioren Training and Research Hospital, Ministry of Health, Ankara, 2Department of Dermatology, Tayfur Ata Sokmen School of Medicine, Mustafa Kemal University, Hatay, 3 Department of Dermatology, School of Medicine, Afyon Kocatepe University, Afyon,Turkey, 4Department of Endocrinology, Tayfur Ata Sokmen School of Medicine, Mustafa Kemal University, Hatay, and 5Ankara Training and Research Hospital, Ministry of Health, Department of Dermatology, Ankara, Turkey
Abstract Background Post-adolescent acne has been defined as acne in a patient aged >25 years. Acne vulgaris first develops at the onset of puberty as a result of hormonal changes. During puberty, there is a transient decline in insulin sensitivity. We hypothesized that insulin resistance might persist after puberty in patients with post-adolescent acne. Objectives This study was conducted in order to investigate the relationship between post-adolescent acne and insulin resistance. Methods The study population comprised 35 patients with post-adolescent acne and 35 healthy control subjects. The parameters measured were fasting blood glucose, insulin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). The homeostasis model assessment of insulin resistance (HOMA-IR)
Correspondence Ilknur Balta, MD Department of Dermatology Kecioren Training and Research Hospital Ministry of Health, Ankara 06290 Turkey E-mail: [email protected]
index was calculated for each individual.
Funding: None. Conflicts of interest: None.
the use of cosmetics, drugs, and environmental factors should be considered in the
Results No significant differences were observed between patients with post-adolescent acne and control subjects in fasting blood glucose, fasting insulin, AST, ALT, triglyceride and HDL-C levels, and HOMA-IR index. There were also no correlations between these parameters and the severity of acne. Conclusions This study suggests that insulin resistance may not play a major role in the pathogenesis of post-adolescent acne. Hormonal changes, genetic susceptibility, stress, development of post-adolescent acne.
doi: 10.1111/ijd.12426
Introduction Acne is usually recognized as a disorder of adolescence. However, the prevalence of adult patients with acne is increasing. Traditionally, post-adolescent acne has been defined as acne in an individual beyond the age of 25 years.1–5 Post-adolescent acne is more common in women.6 It affects approximately 14% of women between the ages of 25 and 50 years. It is described as a predominantly inflammatory, mild-to-moderate form, characterized by papules and pustules, mainly located on the lower third of the face, jaw line, and neck, with rare and non-prominent comedonal lesions.6,7 The pathogenesis of post-adolescent acne is still not exactly understood. The role of circulating hormones remains controversial. Several hormones implicated in the regulation of sebaceous gland activity have been related to acne. These include androgens, estrogens, progesterone, growth hormone, insulin, insulin-like growth factor-1 (IGF-1), corticotroª 2014 The International Society of Dermatology
pin-releasing hormone, adrenocorticotropic hormone, melanocortins, and glucocorticoids.7–9 The role of insulin in the development of acne is also supported by the high prevalence of acne in women with polycystic ovary syndrome (PCOS), a condition associated with insulin resistance, hyperinsulinemia, and hyperandrogenism. Clinical and experimental evidence suggests that insulin resistance and compensatory hyperinsulinemia represent the underlying disturbance in PCOS because insulin resistance generally precedes and gives rise to hyperandrogenism. Insulin and IGF-1 have been shown to stimulate adrenal androgen synthesis and inhibit the hepatic production of sex hormone-binding globulin, allowing for an increase in androgen bioavailability. Treatments aimed at reducing insulin secretion and/or increasing insulin sensitivity, such as with metformin or acarbose, have been demonstrated to reduce serum androgen levels and gonadotrophins, and to improve acne and hirsutism, the menstrual cycle, ovulation, and fertility.8,9 International Journal of Dermatology 2014
1
2
Report
Balta et al.
Insulin resistance in post-adolescent acne
Even without overt PCOS, women with post-adolescent acne maintain elevated serum concentrations of IGF-1 and are mildly insulin-resistant.10 Clinically, IGF-1 has also been shown to correlate with acne lesion counts in adult women, and significantly higher IGF-1 levels have been described in women with acne compared with control subjects.11 The link between sebaceous gland activity and puberty has been recognized for many years. Sebum production begins during puberty and corresponds to peaks in the levels of growth hormone and IGF-1 that occur in midpuberty.9 During puberty, there is also a transient decline in insulin sensitivity. Acne begins about the same time as the gradual increase in plasma insulin, the pre-adolescent increase in body mass index (BMI) and the increase in IGF-1 concentrations. Acne incidence corresponds more closely to the changing course of insulin and IGF-1 levels than it does to changes in plasma androgens. This is because insulin and IGF-1 levels peak during late puberty and gradually decline until the third decade. Acne generally resolves by this time, although circulating androgens remain unchanged.9,12,13 We hypothesized that insulin resistance might also persist after puberty in patients with post-adolescent acne. Thus, insulin resistance might contribute to the development of post-adolescent acne. Therefore, we aimed to investigate the relationship between post-adolescent acne and insulin resistance in this study. Materials and methods The study population comprised 35 patients with post-
time after the age of 25 years is called “late-onset postadolescent acne.”6,7 The BMI was calculated by dividing the subject’s body weight (kg) by the square of his or her height (m2). Venous blood was collected in EDTA tubes after a 12-hour fast. The parameters measured were fasting blood glucose, fasting insulin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Normal ranges for these parameters were accepted as follows: fasting blood glucose: 74–106 mg/dl; fasting insulin: 6–27 lIU/ml; AST: 0–35 IU/l; ALT: 0–35 IU/l; TC: 0–200 mg/dl; triglycerides: 0–150 mg/dl; HDL-C: 40–60 mg/dl; and LDL-C: 0–130 mg/dl. The criteria used to define insulin resistance according to the published guidelines proposed by the European Group for the Study of Insulin Resistance. The homeostasis model assessment of insulin resistance (HOMA-IR) index (fasting insulin 9 fasting blood glucose/405) was calculated for each individual.15
Statistical analysis Statistical analyses were performed using SPSS Version 17.0 (SPSS, Inc., Chicago, IL, USA). All numeric variables are expressed as the mean standard deviation (SD). The statistical significance of differences between groups was determined using an independent-samples t-test. The chisquared test was used for proportional correlations. Correlation analysis between serum fasting glucose, fasting insulin, HOMAIR index, and acne severity was performed using one-way analysis of variance (ANOVA). A P-value of 0.05). The mean duration of acne was 8.5 years (range: 1– 25 years). Eighteen (51.4%) patients had mild, 14 (40.0%) had moderate, and three (8.6%) had severe acne. In 48.6% of patients, only the face was involved; in 22.9% the face and neck were involved; and in 28.6% the face and back were involved. A total of 22 (62.9%) patients had late-onset acne, and 13 (37.1%) had persistent acne. Laboratory findings in the study groups are ª 2014 The International Society of Dermatology
Balta et al.
Insulin resistance in post-adolescent acne
Table 1 Sociodemographic characteristics of patients with post-adolescent acne and healthy control subjects
Characteristic
Patient group (n = 35)
Control group (n = 35)
Gender, n (%) Female 26 (74.3%) Male 9 (25.7%) Age, years, mean SD Female subjects 31.38 5.65 Male subjects 29.22 4.46 All subjects 30.82 5.39 Body mass index, mean SD Female subjects 24.16 4.28 Male subjects 25.92 2.62 All subjects 24.61 3.96
P-value (chi-squared test)
25 (71.4%) 10 (28.6%)
0.78
32.08 6.27 27.60 2.27 30.80 5.77
0.67 0.34 0.98
24.96 4.56 25.10 2.64 25.01 4.07
0.51 0.50 0.68
SD, standard deviation. Table 2 Comparison of laboratory findings in patients with post-adolescent acne and healthy control subjects
Parameter Body mass index, kg/m2 Fasting blood glucose, mg/dl Insulin, lIU/ml HOMA-IR AST, IU/l ALT, IU/l Total cholesterol, mg/dl LDL-C, mg/dl HDL-C, mg/dl Triglycerides, mg/dl
Patient group (n = 35) Mean ± SD
Control group (n = 35) Mean ± SD
24.6 3.9 89.7 7.4
25.0 4.0 90.0 12.6
0.68 0.90
0.41 0.51 0.77 0.37 0.04a 0.01a 0.91 0.12
9.0 2.0 21.0 18.9 189.4 118.0 53.4 123.7
4.9 1.2 6.4 13.4 38.8 32.8 19.6 94.6
9.8 2.1 21.5 22.3 169.8 96.6 53.0 94.0
3.5 0.8 8.5 17.9 42.1 38.6 12.2 59.5
P-value
SD, standard deviation; HOMA-IR, homeostasis model assessment of insulin resistance; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HDL-C, high-density lipoprotein; LDL-C, low-density lipoprotein. a P < 0.05.
summarized in Table 2. No significant differences were observed between patients with post-adolescent acne and control subjects in fasting blood glucose, fasting insulin, AST, ALT, triglyceride and HDL-C levels, and the HOMA-IR index. Serum TC and LDL-C levels were significantly increased in patients with post-adolescent acne (P = 0.04 and P = 0.01, respectively). There were no significant correlations between acne severity and any of fasting blood glucose (P = 0.39), fasting insulin (P = 0.07), TC (P = 0.18), triglyceride (P = 0.18), HDLC (P = 0.49) and LDL-C (P = 0.15) values, or the HOMA-IR index (P = 0.07). ª 2014 The International Society of Dermatology
Report
Discussion Acne vulgaris has been proposed to be a disease mediated by IGF-1. IGF-1 rises during puberty through the action of increased growth hormone secretion and correlates well with the clinical course of acne. Insulin/IGF-1 receptors are expressed in epidermal keratinocytes. Therefore, hyperinsulinemia may lead to an increased proliferation of basal keratinocytes within the pilosebaceous duct and abnormal desquamation of follicular corneocytes. IGF-1 stimulates 5a-reductase, adrenal and gonadal androgen synthesis, androgen receptor signal transduction, sebocyte proliferation, and lipogenesis.9 Blood glucose levels have been reported to be elevated in patients with acne vulgaris in comparison with healthy controls. This occurs primarily because an increase in blood glucose levels stimulates the secretion of insulin, which decreases the binding protein for IGF-1, facilitating the effects of IGF-1 on cell proliferation. High insulin concentrations in the fasting and/or post-prandial states may exacerbate acne by increasing the proliferation of basal keratinocytes. Insulin also stimulates the synthesis of androgens, leading to high sebum production, a recognized correlate of acne severity.16,17 Although dietary factors have long been considered unimportant, insulin resistance and dietary carbohydrates have recently been implicated in the etiology of acne. The glycemic index (GI) of meals has been directly correlated to insulin response, and low GI diets have been shown to decrease insulin resistance.18 Smith et al.12 showed that a low GI diet induced an improvement in acne severity and a parallel improvement in insulin sensitivity in young males with acne vulgaris. By contrast, a study by Reynolds et al.18 suggested that a low GI diet does not significantly improve facial acne any more than a macronutrientmatched high GI diet, although there was a trend for the low GI diet to improve acne to a greater extent than the high GI diet. Reynolds et al.18 also showed that a low GI diet did not induce an improvement in insulin sensitivity in young males with acne vulgaris. Low GI carbohydrates were not responsible for the improvements in facial acne reported by Smith et al.12 Increased weight loss, and higher protein and fiber intake may explain the declines in fasting insulin and HOMA-IR indices. Insulin resistance is known to represent an impaired biological response to either exogenous or endogenous insulin. Although the glucose–insulin relationship is clinically pertinent, it is also important to recognize that, conceptually, insulin resistance does not have to be confined to the parameters of the glucose metabolism. The concept of insulin resistance should apply to any of the biological actions of insulin and might include its effects on lipid and protein metabolism, vascular endothelial function International Journal of Dermatology 2014
3
4
Report
Balta et al.
Insulin resistance in post-adolescent acne
and gene expression.19–21 The reference standard for the evaluation of insulin sensitivity is the glucose clamp test. However, this test is limited to research use and is difficult to perform at all medical institutions.15 Homeostasis model assessment, first described by Matthews et al.,15 is a method for estimating insulin sensitivity. In this study, insulin resistance was evaluated using the HOMA-IR index in patients with post-adolescent acne. We showed that post-adolescent acne is not associated with insulin resistance. In addition, there were no significant differences between fasting blood glucose or fasting insulin levels, or HOMA-IR indices, and acne severity. Kaymak et al.22 reported that serum glucose, insulin levels, and HOMA-IR indices in younger patients with acne vulgaris and control subjects did not differ significantly, which represents a set of findings similar to those in the present study. In addition, Kaymak et al.22 did not find any statistically significant association between acne severity and insulin resistance. Cetin€ ozman et al.23 evaluated androgens and insulin sensitivity markers before and after treatment with isotretinoin in women with severe post-adolescent acne. They reported that all parameters were similar in patients and controls at baseline.23 Isotretinoin therapy increased BMI and triglyceride levels without any effect on androgens or insulin sensitivity. As a result, these authors reported that severe acne itself is not associated with hyperandrogenemia or insulin resistance.23 Ertugrul et al.24 also reported that three months of isotretinoin treatment did not change insulin sensitivity in patients with acne vulgaris. By contrast with these studies, Del Prete et al.13 reported fasting blood glucose, insulin levels, and HOMA-IR indices to be elevated in young males with acne vulgaris compared with healthy controls. The relationships between blood lipids such as TC and triglycerides, and acne are not clear. Akawi et al.25 found that TC levels were not significantly increased but that LDL-C levels were significantly increased in patients with severe acne vulgaris in comparison with controls. However, Arora et al.26 found that TC and LDL-C levels were significantly increased in patients with severe acne. Similarly, we found that serum TC and LDL-C levels were significantly increased in post-adolescent acne patients. Previous studies found that serum HDL-C levels were significantly decreased in acne patients.25–27 By contrast with the findings reported in the literature, we did not find any statistically significant difference in serum HDLC levels between subjects with and without post-adolescent acne. In accordance with other studies,25–27 we found no statistically significant difference in serum triglyceride levels between acne patients and control subjects. These differences may reflect the effects on serum lipid concentrations of dietary habit, socioeconomic status, smoking habit, and racial and genetic factors. International Journal of Dermatology 2014
The major limitations of the present study concern its comparatively small study population. In addition, the number of patients with severe acne was relatively low compared with the numbers of patients with mild and moderate acne. These proportions reflect the real distribution of acne severity in the population. Conclusions This study suggests that insulin resistance may not play a major role in the pathogenesis of post-adolescent acne. Hormonal changes, genetic susceptibility, stress, the use of cosmetics, the use of drugs, and environmental factors should be considered in the development of post-adolescent acne. References 1 Goodman G. Acne – natural history, facts and myths. Aust Fam Physician 2006; 35: 613–616. 2 Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol 1999; 41: 577–580. 3 Goulden V, Clark SM, Cunliffe WJ. Post-adolescent acne: a review of clinical features. Br J Dermatol 1997; 136: 66–70. 4 Collier CN, Harper JC, Cantrell WC, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol 2008; 58: 56–59. 5 Knaggs HE, Wood EJ, Rizer RL, et al. Post-adolescent acne. Int J Cosmet Sci 2004; 26: 129–138. 6 Khunger N, Kumar C. A clinico-epidemiological study of adult acne: is it different from adolescent acne? Indian J Dermatol Venereol Leprol 2012; 78: 335–341. 7 Capitanio B, Sinagra JL, Bordignon V, et al. Underestimated clinical features of post-adolescent acne. J Am Acad Dermatol 2010; 63: 782–788. 8 Melnik BC, Schmitz G. Role of insulin, insulin-like growth factor-1, hyperglycemic food and milk consumption in the pathogenesis of acne vulgaris. Exp Dermatol 2009; 1: 1–9. 9 Arora MK, Yadav A, Saini V. Role of hormones in acne vulgaris. Clin Biochem 2011; 44: 1035–1040. 10 Aizawa H, Niimura M. Mild insulin resistance during oral glucose tolerance test (OGTT) in women with acne. J Dermatol 1996; 23: 526–529. 11 Aizawa H, Niimura M. Elevated serum insulin-like growth factor-1 (IGF-1) levels in women with post-adolescent acne. J Dermatol 1995; 22: 249–252. 12 Smith RN, Mann NJ, Braue A, et al. A low-glycemic-load diet improves symptoms in acne vulgaris patients: a randomized controlled trial. Am J Clin Nutr 2007; 86: 107–115. 13 Del Prete M, Mauriello MC, Faggiano A, et al. Insulin resistance and acne: a new risk factor for men? Endocrine 2012; 42: 555–560. ª 2014 The International Society of Dermatology
Balta et al.
14 Pochi PE, Shalita AR, Strauss JS, et al. Report of the Consensus Conference on Acne Classification. Washington, DC, March 24–25, 1990. J Am Acad Dermatol 1991; 24: 495–500. 15 Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419. 16 Okita K, Iwahashi H, Kozawa J, et al. Homeostasis model assessment of insulin resistance for evaluating insulin sensitivity in patients with type 2 diabetes on insulin therapy. Endocr J 2013; 60: 283–290. 17 Edmondson SR, Thumiger SP, Werther GA, et al. Epidermal homeostasis: the role of the growth hormone and insulin-like growth factor systems. Endocr Rev 2003; 24: 737–764. 18 Reynolds RC, Lee S, Choi JY, et al. Effect of the glycemic index of carbohydrates on acne vulgaris. Nutrients 2010; 2: 1060–1072. 19 American Diabetes Association. Consensus Development Conference on Insulin Resistance, November 5–6, 1997. Diabetes Care 1998; 21: 310–314. 20 Kiens B, Richter EA. Types of carbohydrate in an ordinary diet affect insulin action and muscle substrates in humans. Am J Clin Nutr 1996; 63: 47–53.
ª 2014 The International Society of Dermatology
Insulin resistance in post-adolescent acne
Report
21 Ludwig DS. The glycemic index: physiological mechanism relating to obesity, diabetes, and cardiovascular disease. JAMA 2002; 8: 2414–2423. 22 Kaymak Y, Adisen E, Ilter N, et al. Dietary glycemic index and glucose, insulin, insulin-like growth factor-I, insulin-like growth factor binding protein 3, and leptin levels in patients with acne. J Am Acad Dermatol 2007; 57: 819–823. 23 Cetinozman F, Yazgan Aksoy D, Elcin G, et al. Insulin sensitivity, androgens and isotretinoin therapy in women with severe acne. J Dermatolog Treat 2013; [Epub ahead of print]. 24 Ertugrul DT, Karadag AS, Tutal E, et al. Isotretinoin does not induce insulin resistance in patients with acne. Clin Exp Dermatol 2011; 36: 124–128. 25 Akawi ZE, Latif NA, Razzak KA, et al. The relationship between blood lipid profile and acne. J Health Sci 2007; 53: 596–599. 26 Arora MK, Seth S, Dayal S. The relationship of lipid profile and menstrual cycle with acne vulgaris. Clin Biochem 2010; 43: 1415–1420. 27 Vergani C, Finzi AF, Pigatto PD, et al. Low levels of HDL in severe cystic acne. N Engl J Med 1982; 307: 1151–1152.
International Journal of Dermatology 2014
5
Insulin resistance in patients with post-adolescent acne Ilknur Balta1, MD, Ozlem Ekiz2, MD, Pınar Ozuguz3, MD, Ihsan Ustun4, MD, Semsettin Karaca3, MD, Seval Dogruk Kacar3, MD, and Meral Eksioglu5, MD
1 Department of Dermatology, Kecioren Training and Research Hospital, Ministry of Health, Ankara, 2Department of Dermatology, Tayfur Ata Sokmen School of Medicine, Mustafa Kemal University, Hatay, 3 Department of Dermatology, School of Medicine, Afyon Kocatepe University, Afyon,Turkey, 4Department of Endocrinology, Tayfur Ata Sokmen School of Medicine, Mustafa Kemal University, Hatay, and 5Ankara Training and Research Hospital, Ministry of Health, Department of Dermatology, Ankara, Turkey
Abstract Background Post-adolescent acne has been defined as acne in a patient aged >25 years. Acne vulgaris first develops at the onset of puberty as a result of hormonal changes. During puberty, there is a transient decline in insulin sensitivity. We hypothesized that insulin resistance might persist after puberty in patients with post-adolescent acne. Objectives This study was conducted in order to investigate the relationship between post-adolescent acne and insulin resistance. Methods The study population comprised 35 patients with post-adolescent acne and 35 healthy control subjects. The parameters measured were fasting blood glucose, insulin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). The homeostasis model assessment of insulin resistance (HOMA-IR)
Correspondence Ilknur Balta, MD Department of Dermatology Kecioren Training and Research Hospital Ministry of Health, Ankara 06290 Turkey E-mail: [email protected]
index was calculated for each individual.
Funding: None. Conflicts of interest: None.
the use of cosmetics, drugs, and environmental factors should be considered in the
Results No significant differences were observed between patients with post-adolescent acne and control subjects in fasting blood glucose, fasting insulin, AST, ALT, triglyceride and HDL-C levels, and HOMA-IR index. There were also no correlations between these parameters and the severity of acne. Conclusions This study suggests that insulin resistance may not play a major role in the pathogenesis of post-adolescent acne. Hormonal changes, genetic susceptibility, stress, development of post-adolescent acne.
doi: 10.1111/ijd.12426
Introduction Acne is usually recognized as a disorder of adolescence. However, the prevalence of adult patients with acne is increasing. Traditionally, post-adolescent acne has been defined as acne in an individual beyond the age of 25 years.1–5 Post-adolescent acne is more common in women.6 It affects approximately 14% of women between the ages of 25 and 50 years. It is described as a predominantly inflammatory, mild-to-moderate form, characterized by papules and pustules, mainly located on the lower third of the face, jaw line, and neck, with rare and non-prominent comedonal lesions.6,7 The pathogenesis of post-adolescent acne is still not exactly understood. The role of circulating hormones remains controversial. Several hormones implicated in the regulation of sebaceous gland activity have been related to acne. These include androgens, estrogens, progesterone, growth hormone, insulin, insulin-like growth factor-1 (IGF-1), corticotroª 2014 The International Society of Dermatology
pin-releasing hormone, adrenocorticotropic hormone, melanocortins, and glucocorticoids.7–9 The role of insulin in the development of acne is also supported by the high prevalence of acne in women with polycystic ovary syndrome (PCOS), a condition associated with insulin resistance, hyperinsulinemia, and hyperandrogenism. Clinical and experimental evidence suggests that insulin resistance and compensatory hyperinsulinemia represent the underlying disturbance in PCOS because insulin resistance generally precedes and gives rise to hyperandrogenism. Insulin and IGF-1 have been shown to stimulate adrenal androgen synthesis and inhibit the hepatic production of sex hormone-binding globulin, allowing for an increase in androgen bioavailability. Treatments aimed at reducing insulin secretion and/or increasing insulin sensitivity, such as with metformin or acarbose, have been demonstrated to reduce serum androgen levels and gonadotrophins, and to improve acne and hirsutism, the menstrual cycle, ovulation, and fertility.8,9 International Journal of Dermatology 2014
1
2
Report
Balta et al.
Insulin resistance in post-adolescent acne
Even without overt PCOS, women with post-adolescent acne maintain elevated serum concentrations of IGF-1 and are mildly insulin-resistant.10 Clinically, IGF-1 has also been shown to correlate with acne lesion counts in adult women, and significantly higher IGF-1 levels have been described in women with acne compared with control subjects.11 The link between sebaceous gland activity and puberty has been recognized for many years. Sebum production begins during puberty and corresponds to peaks in the levels of growth hormone and IGF-1 that occur in midpuberty.9 During puberty, there is also a transient decline in insulin sensitivity. Acne begins about the same time as the gradual increase in plasma insulin, the pre-adolescent increase in body mass index (BMI) and the increase in IGF-1 concentrations. Acne incidence corresponds more closely to the changing course of insulin and IGF-1 levels than it does to changes in plasma androgens. This is because insulin and IGF-1 levels peak during late puberty and gradually decline until the third decade. Acne generally resolves by this time, although circulating androgens remain unchanged.9,12,13 We hypothesized that insulin resistance might also persist after puberty in patients with post-adolescent acne. Thus, insulin resistance might contribute to the development of post-adolescent acne. Therefore, we aimed to investigate the relationship between post-adolescent acne and insulin resistance in this study. Materials and methods The study population comprised 35 patients with post-
time after the age of 25 years is called “late-onset postadolescent acne.”6,7 The BMI was calculated by dividing the subject’s body weight (kg) by the square of his or her height (m2). Venous blood was collected in EDTA tubes after a 12-hour fast. The parameters measured were fasting blood glucose, fasting insulin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Normal ranges for these parameters were accepted as follows: fasting blood glucose: 74–106 mg/dl; fasting insulin: 6–27 lIU/ml; AST: 0–35 IU/l; ALT: 0–35 IU/l; TC: 0–200 mg/dl; triglycerides: 0–150 mg/dl; HDL-C: 40–60 mg/dl; and LDL-C: 0–130 mg/dl. The criteria used to define insulin resistance according to the published guidelines proposed by the European Group for the Study of Insulin Resistance. The homeostasis model assessment of insulin resistance (HOMA-IR) index (fasting insulin 9 fasting blood glucose/405) was calculated for each individual.15
Statistical analysis Statistical analyses were performed using SPSS Version 17.0 (SPSS, Inc., Chicago, IL, USA). All numeric variables are expressed as the mean standard deviation (SD). The statistical significance of differences between groups was determined using an independent-samples t-test. The chisquared test was used for proportional correlations. Correlation analysis between serum fasting glucose, fasting insulin, HOMAIR index, and acne severity was performed using one-way analysis of variance (ANOVA). A P-value of 0.05). The mean duration of acne was 8.5 years (range: 1– 25 years). Eighteen (51.4%) patients had mild, 14 (40.0%) had moderate, and three (8.6%) had severe acne. In 48.6% of patients, only the face was involved; in 22.9% the face and neck were involved; and in 28.6% the face and back were involved. A total of 22 (62.9%) patients had late-onset acne, and 13 (37.1%) had persistent acne. Laboratory findings in the study groups are ª 2014 The International Society of Dermatology
Balta et al.
Insulin resistance in post-adolescent acne
Table 1 Sociodemographic characteristics of patients with post-adolescent acne and healthy control subjects
Characteristic
Patient group (n = 35)
Control group (n = 35)
Gender, n (%) Female 26 (74.3%) Male 9 (25.7%) Age, years, mean SD Female subjects 31.38 5.65 Male subjects 29.22 4.46 All subjects 30.82 5.39 Body mass index, mean SD Female subjects 24.16 4.28 Male subjects 25.92 2.62 All subjects 24.61 3.96
P-value (chi-squared test)
25 (71.4%) 10 (28.6%)
0.78
32.08 6.27 27.60 2.27 30.80 5.77
0.67 0.34 0.98
24.96 4.56 25.10 2.64 25.01 4.07
0.51 0.50 0.68
SD, standard deviation. Table 2 Comparison of laboratory findings in patients with post-adolescent acne and healthy control subjects
Parameter Body mass index, kg/m2 Fasting blood glucose, mg/dl Insulin, lIU/ml HOMA-IR AST, IU/l ALT, IU/l Total cholesterol, mg/dl LDL-C, mg/dl HDL-C, mg/dl Triglycerides, mg/dl
Patient group (n = 35) Mean ± SD
Control group (n = 35) Mean ± SD
24.6 3.9 89.7 7.4
25.0 4.0 90.0 12.6
0.68 0.90
0.41 0.51 0.77 0.37 0.04a 0.01a 0.91 0.12
9.0 2.0 21.0 18.9 189.4 118.0 53.4 123.7
4.9 1.2 6.4 13.4 38.8 32.8 19.6 94.6
9.8 2.1 21.5 22.3 169.8 96.6 53.0 94.0
3.5 0.8 8.5 17.9 42.1 38.6 12.2 59.5
P-value
SD, standard deviation; HOMA-IR, homeostasis model assessment of insulin resistance; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HDL-C, high-density lipoprotein; LDL-C, low-density lipoprotein. a P < 0.05.
summarized in Table 2. No significant differences were observed between patients with post-adolescent acne and control subjects in fasting blood glucose, fasting insulin, AST, ALT, triglyceride and HDL-C levels, and the HOMA-IR index. Serum TC and LDL-C levels were significantly increased in patients with post-adolescent acne (P = 0.04 and P = 0.01, respectively). There were no significant correlations between acne severity and any of fasting blood glucose (P = 0.39), fasting insulin (P = 0.07), TC (P = 0.18), triglyceride (P = 0.18), HDLC (P = 0.49) and LDL-C (P = 0.15) values, or the HOMA-IR index (P = 0.07). ª 2014 The International Society of Dermatology
Report
Discussion Acne vulgaris has been proposed to be a disease mediated by IGF-1. IGF-1 rises during puberty through the action of increased growth hormone secretion and correlates well with the clinical course of acne. Insulin/IGF-1 receptors are expressed in epidermal keratinocytes. Therefore, hyperinsulinemia may lead to an increased proliferation of basal keratinocytes within the pilosebaceous duct and abnormal desquamation of follicular corneocytes. IGF-1 stimulates 5a-reductase, adrenal and gonadal androgen synthesis, androgen receptor signal transduction, sebocyte proliferation, and lipogenesis.9 Blood glucose levels have been reported to be elevated in patients with acne vulgaris in comparison with healthy controls. This occurs primarily because an increase in blood glucose levels stimulates the secretion of insulin, which decreases the binding protein for IGF-1, facilitating the effects of IGF-1 on cell proliferation. High insulin concentrations in the fasting and/or post-prandial states may exacerbate acne by increasing the proliferation of basal keratinocytes. Insulin also stimulates the synthesis of androgens, leading to high sebum production, a recognized correlate of acne severity.16,17 Although dietary factors have long been considered unimportant, insulin resistance and dietary carbohydrates have recently been implicated in the etiology of acne. The glycemic index (GI) of meals has been directly correlated to insulin response, and low GI diets have been shown to decrease insulin resistance.18 Smith et al.12 showed that a low GI diet induced an improvement in acne severity and a parallel improvement in insulin sensitivity in young males with acne vulgaris. By contrast, a study by Reynolds et al.18 suggested that a low GI diet does not significantly improve facial acne any more than a macronutrientmatched high GI diet, although there was a trend for the low GI diet to improve acne to a greater extent than the high GI diet. Reynolds et al.18 also showed that a low GI diet did not induce an improvement in insulin sensitivity in young males with acne vulgaris. Low GI carbohydrates were not responsible for the improvements in facial acne reported by Smith et al.12 Increased weight loss, and higher protein and fiber intake may explain the declines in fasting insulin and HOMA-IR indices. Insulin resistance is known to represent an impaired biological response to either exogenous or endogenous insulin. Although the glucose–insulin relationship is clinically pertinent, it is also important to recognize that, conceptually, insulin resistance does not have to be confined to the parameters of the glucose metabolism. The concept of insulin resistance should apply to any of the biological actions of insulin and might include its effects on lipid and protein metabolism, vascular endothelial function International Journal of Dermatology 2014
3
4
Report
Balta et al.
Insulin resistance in post-adolescent acne
and gene expression.19–21 The reference standard for the evaluation of insulin sensitivity is the glucose clamp test. However, this test is limited to research use and is difficult to perform at all medical institutions.15 Homeostasis model assessment, first described by Matthews et al.,15 is a method for estimating insulin sensitivity. In this study, insulin resistance was evaluated using the HOMA-IR index in patients with post-adolescent acne. We showed that post-adolescent acne is not associated with insulin resistance. In addition, there were no significant differences between fasting blood glucose or fasting insulin levels, or HOMA-IR indices, and acne severity. Kaymak et al.22 reported that serum glucose, insulin levels, and HOMA-IR indices in younger patients with acne vulgaris and control subjects did not differ significantly, which represents a set of findings similar to those in the present study. In addition, Kaymak et al.22 did not find any statistically significant association between acne severity and insulin resistance. Cetin€ ozman et al.23 evaluated androgens and insulin sensitivity markers before and after treatment with isotretinoin in women with severe post-adolescent acne. They reported that all parameters were similar in patients and controls at baseline.23 Isotretinoin therapy increased BMI and triglyceride levels without any effect on androgens or insulin sensitivity. As a result, these authors reported that severe acne itself is not associated with hyperandrogenemia or insulin resistance.23 Ertugrul et al.24 also reported that three months of isotretinoin treatment did not change insulin sensitivity in patients with acne vulgaris. By contrast with these studies, Del Prete et al.13 reported fasting blood glucose, insulin levels, and HOMA-IR indices to be elevated in young males with acne vulgaris compared with healthy controls. The relationships between blood lipids such as TC and triglycerides, and acne are not clear. Akawi et al.25 found that TC levels were not significantly increased but that LDL-C levels were significantly increased in patients with severe acne vulgaris in comparison with controls. However, Arora et al.26 found that TC and LDL-C levels were significantly increased in patients with severe acne. Similarly, we found that serum TC and LDL-C levels were significantly increased in post-adolescent acne patients. Previous studies found that serum HDL-C levels were significantly decreased in acne patients.25–27 By contrast with the findings reported in the literature, we did not find any statistically significant difference in serum HDLC levels between subjects with and without post-adolescent acne. In accordance with other studies,25–27 we found no statistically significant difference in serum triglyceride levels between acne patients and control subjects. These differences may reflect the effects on serum lipid concentrations of dietary habit, socioeconomic status, smoking habit, and racial and genetic factors. International Journal of Dermatology 2014
The major limitations of the present study concern its comparatively small study population. In addition, the number of patients with severe acne was relatively low compared with the numbers of patients with mild and moderate acne. These proportions reflect the real distribution of acne severity in the population. Conclusions This study suggests that insulin resistance may not play a major role in the pathogenesis of post-adolescent acne. Hormonal changes, genetic susceptibility, stress, the use of cosmetics, the use of drugs, and environmental factors should be considered in the development of post-adolescent acne. References 1 Goodman G. Acne – natural history, facts and myths. Aust Fam Physician 2006; 35: 613–616. 2 Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol 1999; 41: 577–580. 3 Goulden V, Clark SM, Cunliffe WJ. Post-adolescent acne: a review of clinical features. Br J Dermatol 1997; 136: 66–70. 4 Collier CN, Harper JC, Cantrell WC, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol 2008; 58: 56–59. 5 Knaggs HE, Wood EJ, Rizer RL, et al. Post-adolescent acne. Int J Cosmet Sci 2004; 26: 129–138. 6 Khunger N, Kumar C. A clinico-epidemiological study of adult acne: is it different from adolescent acne? Indian J Dermatol Venereol Leprol 2012; 78: 335–341. 7 Capitanio B, Sinagra JL, Bordignon V, et al. Underestimated clinical features of post-adolescent acne. J Am Acad Dermatol 2010; 63: 782–788. 8 Melnik BC, Schmitz G. Role of insulin, insulin-like growth factor-1, hyperglycemic food and milk consumption in the pathogenesis of acne vulgaris. Exp Dermatol 2009; 1: 1–9. 9 Arora MK, Yadav A, Saini V. Role of hormones in acne vulgaris. Clin Biochem 2011; 44: 1035–1040. 10 Aizawa H, Niimura M. Mild insulin resistance during oral glucose tolerance test (OGTT) in women with acne. J Dermatol 1996; 23: 526–529. 11 Aizawa H, Niimura M. Elevated serum insulin-like growth factor-1 (IGF-1) levels in women with post-adolescent acne. J Dermatol 1995; 22: 249–252. 12 Smith RN, Mann NJ, Braue A, et al. A low-glycemic-load diet improves symptoms in acne vulgaris patients: a randomized controlled trial. Am J Clin Nutr 2007; 86: 107–115. 13 Del Prete M, Mauriello MC, Faggiano A, et al. Insulin resistance and acne: a new risk factor for men? Endocrine 2012; 42: 555–560. ª 2014 The International Society of Dermatology
Balta et al.
14 Pochi PE, Shalita AR, Strauss JS, et al. Report of the Consensus Conference on Acne Classification. Washington, DC, March 24–25, 1990. J Am Acad Dermatol 1991; 24: 495–500. 15 Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419. 16 Okita K, Iwahashi H, Kozawa J, et al. Homeostasis model assessment of insulin resistance for evaluating insulin sensitivity in patients with type 2 diabetes on insulin therapy. Endocr J 2013; 60: 283–290. 17 Edmondson SR, Thumiger SP, Werther GA, et al. Epidermal homeostasis: the role of the growth hormone and insulin-like growth factor systems. Endocr Rev 2003; 24: 737–764. 18 Reynolds RC, Lee S, Choi JY, et al. Effect of the glycemic index of carbohydrates on acne vulgaris. Nutrients 2010; 2: 1060–1072. 19 American Diabetes Association. Consensus Development Conference on Insulin Resistance, November 5–6, 1997. Diabetes Care 1998; 21: 310–314. 20 Kiens B, Richter EA. Types of carbohydrate in an ordinary diet affect insulin action and muscle substrates in humans. Am J Clin Nutr 1996; 63: 47–53.
ª 2014 The International Society of Dermatology
Insulin resistance in post-adolescent acne
Report
21 Ludwig DS. The glycemic index: physiological mechanism relating to obesity, diabetes, and cardiovascular disease. JAMA 2002; 8: 2414–2423. 22 Kaymak Y, Adisen E, Ilter N, et al. Dietary glycemic index and glucose, insulin, insulin-like growth factor-I, insulin-like growth factor binding protein 3, and leptin levels in patients with acne. J Am Acad Dermatol 2007; 57: 819–823. 23 Cetinozman F, Yazgan Aksoy D, Elcin G, et al. Insulin sensitivity, androgens and isotretinoin therapy in women with severe acne. J Dermatolog Treat 2013; [Epub ahead of print]. 24 Ertugrul DT, Karadag AS, Tutal E, et al. Isotretinoin does not induce insulin resistance in patients with acne. Clin Exp Dermatol 2011; 36: 124–128. 25 Akawi ZE, Latif NA, Razzak KA, et al. The relationship between blood lipid profile and acne. J Health Sci 2007; 53: 596–599. 26 Arora MK, Seth S, Dayal S. The relationship of lipid profile and menstrual cycle with acne vulgaris. Clin Biochem 2010; 43: 1415–1420. 27 Vergani C, Finzi AF, Pigatto PD, et al. Low levels of HDL in severe cystic acne. N Engl J Med 1982; 307: 1151–1152.
International Journal of Dermatology 2014
5
