International Journal of Endocrinology
Volume 2018 (2018), Article ID 2304746, 7 pages
https://doi.org/10.1155/2018/2304746

Clinical Study

Melatonin Treatment Improves Insulin Resistance and Pigmentation in Obese Patients with Acanthosis Nigricans

Hang Sun,¹ Xingchun Wang,¹ Jiaqi Chen,² Aaron M. Gusdon,3,4 Kexiu Song,¹ Liang Li,¹ and Shen Qu¹

¹Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai 200072, China
²Department of Endocrinology and Metabolism, SuZhou Municipal Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China
³Division of Neuropathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
⁴Department of Neurology, Weill Cornell Medical College, New York, NY 10065, USA

Correspondence should be addressed to Shen Qu; qushencn@hotmail.com

Received 22 August 2017; Revised 21 December 2017; Accepted 10 January 2018; Published 12 March 2018

Academic Editor: Amelie Bonnefond

Copyright © 2018 Hang Sun et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Objective. This study aimed to determine the effects of melatonin on insulin resistance in obese patients with acanthosis nigricans (AN). Methods. A total of 17 obese patients with acanthosis nigricans were recruited in a 12-week pilot open trial. Insulin sensitivity, glucose metabolism, inflammatory factors, and other biochemical parameters before and after the administration of melatonin were measured. Results. After 12 weeks of treatment with melatonin (3 mg/day), homeostasis model assessment insulin resistance index (HOMA-IR) (8.99 ± 5.10 versus 7.77 ± 5.21, ) and fasting insulin (37.09 5 ± 20.26 μU/ml versus 32.10 ± 20.29 μU/ml, ) were significantly decreased. Matsuda index (2.82 ± 1.54 versus 3.74 ± 2.02, ) was significantly increased. There were also statistically significant declines in the AN scores of the neck and axilla, body weight, body mass index, body fat, visceral index, neck circumference, waist circumference, and inflammatory markers. Conclusions. It was concluded that melatonin could improve cutaneous symptoms in obese patients with acanthosis nigricans by improving insulin sensitivity and inflammatory status. This trial is registered with ClinicalTrials.gov NCT02604095.

1. Introduction

Melatonin is a hormone secreted by the pineal gland. The synthesis and secretion of melatonin are regulated by light intensity [1]. Investigations found that melatonin has multiple effects and acts as an antioxidant [2, 3], has anti-inflammatory properties [4, 5], regulates circadian rhythms [6], regulates immunity [7] and has antineoplastic effects [8]. Research also found that melatonin can regulate lipid metabolism [9], increase insulin sensitivity [10], regulate glucose metabolism [11], and reduce body weight [12].

Acanthosis nigricans (AN) is a disease characterized by skin pigmentation, hyperkeratosis, and velvet hyperplasia. Increased pigmentation commonly occurs in the posterior neck, axilla, and groin, and it can also be seen on the cubital fossa, labia, face, and other locations throughout the body [13]. AN can be divided into two categories: benign and malignant [14]. Studies have found that benign AN is closely related to hyperinsulinemia, insulin resistance (IR), and obesity [15, 16]. Many different topical and oral treatments have been attempted for AN. Studies reported that treatment with both metformin and rosiglitazone are useful in AN characterized by IR [17, 18]. Low-calorie diet, increasing physical activity, and weight reduction also can relieve symptoms of AN by improving the IR [19]. However, no safe and effective therapy exists especially when considering young patients with euglycemia. Patients with AN also are at increased risk of developing metabolic disorders such as diabetes and dyslipidemia.

Melatonin can regulate internal biological clocks and energy metabolism [20]. Melatonin influences insulin secretion mediated by Gi-protein-coupled melatonin receptors MT1 and MT2 [21]. It was found that melatonin treatment for one year could reduce fat mass and increase lean mass in postmenopausal women [22]. So this study was designed to determine whether treatment with melatonin is an effective treatment for AN as well as insulin resistance and metabolic disturbances.

2. Materials and Methods

2.1. Study Population

A total of 17 patients (6 males and 11 females, age 27.35 ± 6.50) were enrolled in the 12-week pilot open trial with no placebo group included. The study was approved by the ethical committee of the Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China, and registered by ClinicalTrials.gov (NCT02604095). Inclusion criteria included (1) aging from 18 to 60 years old, (2) having acanthosis nigricans, and (3) body mass index (BMI) exceeding 28 kg/m². Exclusion criteria included (1) malignant acanthosis nigricans; (2) serious renal, adrenal, or hepatic dysfunction; (3) taking medications chronically for systemic illness; (4) lactation; (5) pregnancy; (6) active cancer; (7) taking weight-loss drugs; and (8) history of stomach reduction surgery. Each patient gave written informed voluntary consent before participating in the study.

2.2. Study Design

After the initial screening, age, gender, and height of each participant were recorded. Weight, BMI, and visceral index were measured with light clothes and without shoes using an Omron HBF-358 (Q40102010L01322F, Japan), with the same controlling of water, food, diuretics, alcohol and coffee intake, and urination. Neck circumference (NC), waist circumference (WC), hip circumference (HC), blood pressure (BP), and heart rate (HR) were measured twice, and the average was used for analysis.

Scores of AN were calculated as described previously [23]. There are four degrees from 0 to 4 on the AN scales, which are strongly associated with fasting insulin and BMI.

After overnight fasting, serum glucose, insulin, C-peptide (C-p), lipid profiles, free fatty acids (FFA), uric acid (UA), inflammation factors (c-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 8 (IL-8)), superoxide dismutase (SOD), alanine transaminase (ALT), aspartate transaminase (AST), creatinine (Cr), urea nitrogen (UN), free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) were measured. Participant also underwent a standard 75 g oral glucose-tolerance test (OGTT) after fasting overnight. Samples were collected at 0, 30, 60, 90, and 120 min, and glucose, insulin, and C-p were measured. All these measurements were performed before and after 12 weeks of treatment.

Each patient received 3 mg/day melatonin (Schiff Nutrition Group: each tablet contains melatonin 3 mg, vitamin B6 5 mg, and calcium 52 mg) given orally at bedtime for 12 weeks.

2.3. Statistics and Calculations

All data were analyzed using SPSS 21.0 software (Chicago, IL). The data are presented as the means ± SD or medians (interquartile range) for skewed variables or proportions for categorical variables. Student’s t-tests were used to compare the difference between measured variables. values < 0.05 were considered statistically significant. Insulin resistance and sensitivity were assessed by the homeostasis model assessment insulin resistance index (HOMA-IR; fasting insulin × fasting glucose/22.5) [24] and Matsuda index {1000/(Glu0 × Ins0 × mean-glucose × mean-insulin)1/2} [25].

3. Results

3.1. Insulin Resistance and Sensitivity

As shown in Table 1, melatonin treatment significantly decreased the HOMA-IR (8.99 ± 5.1047 versus 7.77 ± 5.2169, ) and fasting insulin (37.0935 ± 20.26215 versus 32.1018 ± 20.29752 μU/ml, ) levels and induced the Matsuda index (2.82 ± 1.54 versus 3.74 ± 2.02, ). There was no statistically significant change in fasting glucose and fasting C peptide levels.

Table 1: Effects of melatonin on various biochemical indices.

Parameters
Baseline
After 12 weeks of treatment
value

HOMA-IR
8.99 ± 5.1047
7.77 ± 5.2169
0.027

Matsuda index
2.822 ± 1.5423
3.744 ± 2.0238
0.017

FPG, mmol/l
5.365 ± 0.8645
5.341 ± 0.8307
0.839

Glucose 30, mmol/l
9.853 ± 1.9872
9.259 ± 1.8416
0.044

Glucose 60, mmol/l
10.794 ± 2.8203
10.247 ± 2.7405
0.156

Glucose 120, mmol/l
8.341 ± 3.1071
8.071 ± 3.2299
0.340

Glucose 180, mmol/l
5.835 ± 2.4392
5.812 ± 1.6605
0.939

Fasting insulin, μU/ml
37.0935 ± 20.26215
32.1018 ± 20.29752
0.010

Insulin 30, μU/ml
149.8935 ± 54.80039
116.8088 ± 54.59683
<0.01

Insulin 60, μU/ml
170.45 ± 83.12034
143.9794 ± 63.21096
0.006

Insulin 120, μU/ml
160.4506 ± 85.95451
135.0529 ± 92.32970
0.018

Insulin180, μU/ml
80.2476 ± 64.86455
73.1259 ± 67.18857
0.416

Fasting CP, ng/ml
4.8776 ± 1.5665
4.5759 ± 1.4895
0.130

TC, mmol/l
4.9312 ± 0.7684
4.7671 ± 0.7834
0.212

TG, mmol/l
1.9094 ± 0.7576
1.7824 ± 0.8641
0.338

HDL-C, mmol/l
1.1029 ± 0.2911
1.0741 ± 0.2430
0.422

LDL-C, mmol/l
3.0282 ± 0.6262
2.9218 ± 0.4897
0.221

FFA, mmol/l
0.588 ± 0.2233
0.506 ± 0.1600
0.084

UA, μmol/l
443.518 ± 132.5464
432.635 ± 111.2079
0.400

CRP, mg/l
4.6159 ± 3.27755
3.6429 ± 2.89784
0.014

IL-6, pg/ml
15.3318 ± 13.84451
13.8276 ± 10.09683
0.527

IL-8, pg/ml
221.1482 ± 321.43527
177.6976 ± 241.08857
0.328

TNF-α, pg/ml
28.0594 ± 25.81318
16.9288 ± 14.92093
0.040

SOD, U/ml
154.06 ± 15.262
173.35 ± 55.623
0.166

ALT, U/l
47.224 ± 23.7542
42.929 ± 25.7068
0.391

AST, U/l
32.400 ± 16.5831
30.918 ± 13.5636
0.625

Tbil, μmol/l
10.376 ± 5.3582
10.476 ± 5.2538
0.903

ALP, U/l
77.347 ± 38.9236
73.018 ± 37.5913
0.217

Cr, μmol/l
59.641 ± 14.6798
60.959 ± 14.6248
0.312

UN, mmol/l
4.647 ± 1.1906
4.924 ± 1.3796
0.118

fT3, pmol/l
5.1976 ± 0.50209
5.0829 ± 0.55324
0.203

fT4, pmol/l
15.3112 ± 1.32976
15.0959 ± 1.85283
0.515

TSH, pmol/l
2.75288 ± 1.389337
2.43759 ± 1.174457
0.092

.

3.2. Physiological Measures

After 12 weeks of treatment with melatonin, there were statistically significant changes in the AN scores of the neck (3.35 ± 0.862 versus 2.59 ± 0.712, ) and axilla (3.53 ± 0.717 versus 2.65 ± 0.702, ) (Table 2). There were also significant reductions in BMI (35.741 ± 4.7844 versus 34.524 ± 4.7278 kg/m², ), body weight (100.912 ± 22.9884 versus 97.453 ± 21.8012 kg, ), body fat (37.206 ± 5.3743% versus 35.488 ± 6.6078%, ), and visceral index (17.41 ± 6.510 versus 15.82 ± 6.085, ) (Table 2). Pigmentation in patients with AN was improved after treatment (Figure 1). Melatonin also decreased NC (40.718 ± 4.1652 versus 40.118 ± 4.1213 cm, ), WC (111.471 ± 13.7184 versus 107.853 ± 14.2607 cm, ), and HC (114.818 ± 10.6647 versus 113.488 ± 10.5441 cm, ) (Table 2).

Table 2: Physiological measures.

Parameters
Baseline
After 12 weeks of treatment
value

SBP, mmHg
134.18 ± 10.690
131.88 ± 10.787
0.085

DBP, mmHg
87.53 ± 10.967
87.00 ± 11.292
0.478

HR, bmp
85.35 ± 7.533
82.35 ± 9.096
0.174

Weight, kg
100.912 ± 22.9884
97.453 ± 21.8012
0.001

Body fat, %
37.206 ± 5.3743
35.488 ± 6.6078
0.038

BMI, kg/m²
35.741 ± 4.7844
34.524 ± 4.7278
0.001

Visceral index
17.41 ± 6.510
15.82 ± 6.085
0.001

NC, cm
40.718 ± 4.1652
40.118 ± 4.1213
0.045

WC, cm
111.471 ± 13.7184
107.853 ± 14.2607
0.002

HC, cm
114.818 ± 10.6647
113.488 ± 10.5441
0.028

AN score, neck
3.35 ± 0.862
2.59 ± 0.712
<0.01

AN score, axilla
3.53 ± 0.717
2.65 ± 0.702
<0.01

.

(a)

(b)

Figure 1: Effects of melatonin on acanthosis of neck: a typical case. (a) Baseline. (b) After 12 w treatment.

3.3. Lipid and Inflammatory Parameters

As shown in Table 1, there were no significant decreases in serum lipids (TC, TG, LDL-C, and HDL-C). CRP (4.6159 ± 3.27755 versus 3.6429 ± 2.89784 mg/l, ) and TNF-α (28.0594 ± 25.81318 versus 16.9288 ± 14.92093, ) were decreased significantly, but IL-6 and IL-8 did not decrease significantly. There were also no changes in serum SOD, ALT, AST, Cr, UN, fT3, fT4, and TSH (Table 2). The baseline of participants is showed in Table 3.

Table 3: Baseline of participants.

(a)

Number
Sex (1: male; 2: female)
Age (year)
SBP (mmHg)
DBP (mmHg)
HR (bpm)
Height (cm)
Weight (kg)

1
1
18
134
78
89
182
131.4

2
2
19
111
66
69
154
66.4

3
2
37
126
91
103
156
69

4
2
30
125
90
84
158
86.7

5
1
29
146
110
86
166
86.2

6
2
19
130
89
78
152
73.7

7
2
39
142
94
86
155.5
88.6

8
1
34
145
95
82
172
119.8

9
2
29
128
80
89
160
93.9

10
1
28
120
90
89
182
127.6

11
2
24
132
86
92
174
100.2

12
2
25
138
86
78
167
121

13
2
28
135
79
86
165
93.8

14
2
35
136
78
87
160
99.1

15
2
22
149
94
94
178
104.6

16
1
18
132
76
83
175
103.5

17
1
31
152
106
89
183
150

(b)

Number
Fat (%)
BMI (kg/m²)
Visceral index
NC (cm)
WC (cm)
HC (cm)
AN score, neck
AN score, axilla

1
35.5
39.7
24
45.5
120.5
131.2
4
4

2
30.5
28
8
36
90.3
99.5
4
4

3
34.4
28.4
9
39.7
98
96
3
2

4
38.7
34.7
16
42
106.5
119.2
4
4

5
25
31.3
16
41.5
100.2
105
4
4

6
34.2
31.9
10
38.5
98.5
103
4
4

7
42.5
36.6
21
38
110
117
4
4

8
37.7
40.5
30
48.5
130
121
4
4

9
41.9
36.7
19
39
115
109
2
3

10
34.4
38.5
25
45
129
116
4
4

11
40.7
33.1
13
37
108
118
4
4

12
43.6
43.4
27
36
108
132
4
4

13
41
34.5
15
43
105
120
2
2

14
43.2
38.7
22
41.5
115
104
3
3

15
38.9
33
12
35
105
116
3
4

16
29.1
33.8
14
38
110
117
2
3

17
41.2
44.8
15
48
146
128
2
3

4. Discussion

In 2000, AN was established as a formal risk factor for the development of diabetes in children by the American Diabetes Association [16]. Insulin resistance commonly occurs in association with AN.

The cutaneous manifestations of AN are caused by hyperinsulinemia and the stimulation of keratinocytes and dermal fibroblasts by growth factors [26, 27]. Patients with hyperinsulinemia have increased IGF-1 levels [28]. Hyperinsulinemia is able to reduce IGF binding protein- (IGFBP-) 1 and IGFBP-2, which regulate levels of IGFs. Reduced IGFBP-1 and IGFBP-2 levels could increase free IGF-1, thereby promoting the development of papillomatosis and hyperkeratosis observed in AN [29]. There are two membrane receptors of melatonin called MT1 and MT2, which are G-protein-coupled receptors, in the periphery [30]. Both receptors are expressed in the islets of Langerhans and are involved in the regulation of glucagon secretion from α-cells and insulin secretion from β-cells [10]. Numerous studies support that activation of MT1 or MT2 leads to a reduction in second messenger 3,5-cyclic adenosine monophosphate (cAMP) or 3,5-cyclic guano-sine monophosphate (cGMP) accompanied by reduced insulin secretion [31, 32]. Picinato et al. [33] found the effects of melatonin on the phosphorylation of IGF and insulin receptors triggering their signalization cascade. Therefore, the effect of melatonin on insulin secretion and IGF may explain the mechanism of action behind the utility of treating AN with melatonin.

Most patients with AN also have severe obesity. Accumulating evidence shows that obesity is a clinical indicator for the risk of cardiovascular diseases, diabetes mellitus, and the associated metabolic syndrome [34, 35]. Somewhat surprisingly, we found that treatment with melatonin for only 12 weeks significantly decreased body weight, BMI, body fat, and visceral index of obese participants. Previous studies have shown that NC is associated with the metabolic disorders related to insulin resistance, cardiovascular diseases, metabolic syndrome, and obstructive sleep apnea syndrome [36, 37]. Melatonin was also found to decrease NC and WC, which are commonly considered as risk factors for metabolic syndrome.

Numerous studies have demonstrated that melatonin has antioxidant [2, 3] and anti-inflammatory [4] functions. In our study, serum CRP and TNF-α were decreased. Some investigators have suggested that the inflammation induced by metabolic surplus is different from classical inflammation [38]. TNF-α was the first inflammatory marker discovered in adipose tissue of obese mice [39]. As another inflammatory marker, CRP has been shown to be associated with an increased risk for development of type 2 diabetes mellitus (T2DM) [40]. We consider the anti-inflammatory function of melatonin as one of the possible mechanisms by which it improves AN.

This study had several limitations. Firstly, recruitment to diabetes trials has long been associated with placebo-mediated improvements in glycemic control and associated metabolic parameters [41]. But because of the lack resources to perform additional placebo arm studies, we do not have enough ability to recruit placebo-controlled subjects. Secondly, the sample size of the present study was relatively small. Because of the individual difference, we could not see significant changes in lipid metabolism and antioxidation functions. Secondly, we could not measure the overnight urinary 6-sulfatoxymelatonin excretion (UME), which can reflect the level of internal melatonin, of the outpatients. Further studies are necessary to prove these conclusions.

5. Conclusion

In summary, treatment with melatonin can decrease weight, adipose tissues, and cutaneous symptoms in obese patients with AN. It may act through improvement of insulin resistance and decreasing inflammation. However, further work must be done to elucidate its complete mechanism of action.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Hang Sun, Xingchun Wang, and Jiaqi Chen contributed equally to this work.

Acknowledgments

The present study would not have been possible without the participation of the patients. The abstract of this research has been published in ADA in 2016. This study is supported by the Program for Outstanding Medical Academic Leader, Central University Cross Fund, and Chinese Medical Association Fund (nos. 12020550355 and 22120170145).

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