The Clinical Characteristics of Obese Patients with Acanthosis Nigricans and Its Independent Risk Factors

• Abstract
• Introduction
• Patients and Methods
• Patients
• Diagnostic criteria for AN
• Methods
• Statistical analysis
• Results
• Discussion
• Conclusions
• Authors’ Contribution
• References

Abstract

Objective: This study aimed to investigate the clinical characteristics and risk factors for acanthosis nigricans (AN) in obese patients.

Methods: 80 obese patients without AN (OB group) and 128 obese patients with AN (AN group) were included in this study. Clinical data for each patients were collected. Serum levels of leptin were measured by ELISA.

Results: Body mass index (BMI), uric acid (UA) levels, fasting insulin, and HOMA-IR were higher in AN than OB (P<0.05). The levels of leptin were significantly higher in AN than OB (P<0.001) after adjustment for BMI and gender. In male patients, AN showed lower serum levels of testosterone than OB (P<0.001). Multiple Logistic-regression analysis demonstrated that UA (OR 4.627, 95%CI 2.443–8.762, P<0.001) and Leptin (OR 4.098, 95%CI 1.237–13.581, P=0.021) were independent risk factors for AN. In addition, low testosterone level was an independent risk factor for AN in male obese patients (OR 39.062, 95%CI 5.523–283.808, P<0.001).

Conclusions: AN is associated with more severe hyperinsulinemia and hyperuricemia in obese patients, as well as lower serum testosterone levels in male patients. UA and Leptin were independent risk factors for AN in obese patients. Low testosterone may be a valuable predictor of AN in male obese patients.

Introduction

Obesity is a global public health challenge, and it is linked to the development of multiple metabolic disorders [1]. Acanthosis nigricans (AN) is characterized by hyperpigmented and papillose thickening of the epidermis, which is mainly present on the skin folds, such as the axillae, posterior neck, umbilicus, and occasionally mucosal surfaces [2] [3]. Clinical studies have shown that AN is usually accompanied by metabolic disorders, including obesity, diabetes, hyperinsulinemia, hyperlipidemia, and insulin resistance [2]. Insulin resistance is regarded as the key mechanism that leads to the development of AN in obesity. In turn, AN is a physical marker of insulin resistance and of more profound underlying metabolic alterations in obese patients [4] [5]. However, an incomplete understanding of the mechanisms leading to AN remains a major hurdle for the development of new and effective treatment strategies.

Leptin, a hormone secreted by adipocytes and expressed in tissues such as placenta, ovaries, skeletal muscle, stomach, and liver [6], has been shown to regulate food intake and energy expenditure through a variety of neural and endocrine mechanisms [7]. Leptin and insulin are closely associated with obesity and its complications like nonalcoholic fatty liver disease (NAFLD) [8]. Leptin acts primarily on the hypothalamus to stimulate a variety of catabolic pathways [9] [10]. In addition, leptin could also promote cellular proliferation.

Uric acid (UA) is present at high levels in human plasma and has been shown to have antioxidant properties [11]. Conversely, UA also has proxidant properties, and contributes to the development of many metabolic diseases such as type 2 diabetes and cardiovascular disease [12]. UA is believed to contribute to the development of type 2 diabetes by inhibiting the bioavailability of nitric oxide and thereby inhibiting insulin secretion [13] [14]. Increased levels of serum UA have also been associated with higher risk of diabetic complications, including neuropathy [15], diabetic retinopathy [16], nephropathy [17] and microvascular complications [18] [19].

The present study aims to investigate the differences in metabolism including leptin in obese patients with or without AN. We also sought to identify biomarkers and risk factors for the development of AN in obese patients.

Patients and Methods

Patients

The present study based on data from outpatients of Shanghai Tenth People’s Hospital was conducted among obese patients between August 2013 and May 2015. 80 obese patients without AN and 128 obese patients with AN aged from 18 to 36 years old were included. Obesity was defined as BMI≥28 kg/m². Approval for the study was obtained from the Ethics Committee of the Shanghai Tenth People’s Hospital. The Clinical Trials Registration Number is ChiCTR-OCS-12002381, and all the participants were asked to sign an informed consent prior to participation in the study.

Patients with medical illnesses such as clinical or laboratory evidence of cardiac, renal, liver, or severe systemic diseases (e. g., cancer and heart failure) were excluded.

Diagnostic criteria for AN

The following scale for AN was used [20]. Neck severity: 0-Absent, not detectable on close inspection; 1-Present, clearly present on close visual inspection, not visible to the casual observer, extent not measurable; 2-Mild, limited to the base of the skull, does not extend to the lateral margins of the neck (usually <3 inches in breadth); 3-Moderate, extending to the lateral margins of the neck (posterior border of the sternocleidomastoid, usually 3–6 inches), not be visible when the participant is viewed from the front; 4-Severe, extending anteriorly (>6 inches), visible when the participant is viewed from the front. In this study, each subject enrolled with AN had a score greater than 2.

Methods

Blood samples were obtained between 07:00 AM and 10:00 AM after 10 h of fasting. Serum was separated and stored at −80°C until further analysis. Total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), uric acid (UA) and oral glucose tolerance test (OGTT) were measured. In addition, free testosterone was measured in males only. The homeostasis model of assessment for insulin resistance (HOMA-IR) was calculated on the basis of fasting values of plasma glucose and insulin according to the HOMA model formula: HOMA-IR=fasting insulin×fasting glucose, divided by 22.5 [21]. Serum leptin levels were measured after an overnight fasting by ELISA (R&D)

Statistical analysis

All statistical analysis was performed with IBM SPSS version 18.0 for Windows (IBM Corporation, Armonk, NY). Quantitative data were presented as mean±standard deviation (SD) and the count data as the number of columns (n). Independent samples Student’s t tests were used for statistical comparisons. Pearson or Spearman methods were used for correlation analysis to assess the correlation between leptin and other variables. Analysis of covariance (ANCOVA) was applied to determine the difference in serum leptin between the 2 groups after adjusting BMI and gender. Logistic-regression analysis was performed to determine the risk factors for AN. A P-value of less than 0.05 was considered statistically significant.

Results

The general characteristics and demographics of the patients are displayed in [Table 1]. There was no statistically significant difference in age, FFA, TC, TG, and blood glucose between the 2 groups. Compared with the OB group, the AN group had increased UA (P<0.001), CRP (P=0.016), plasma insulin levels (at 0 min, 30 min, 60 min, (P<0.001), and 120 min (P=0.001)), C-peptide at each point (P≤0.001), and HOMA-IR (P=0.008).

AN patients had higher serum levels (34.74±2.95 ng/ml) of leptin than the OB group (26.25±2.74 ng/ml) (P<0.001) after adjusting for BMI and gender ([Table 2]).

In male patients, the AN group had lower serum of testosterone than OB group (7.89±3.35 nmol/l vs 12.72±3.57 nmol/l, respectively) (P<0.001). The two groups showed no significant difference in E2 and progesterone levels (P=0.239, and 0.177 respectively) ([Table 3]).

Serum level of leptin was correlated with BMI (P<0.001), plasma insulin 0 min, 30 min, 60 min, 120 min, 180 min (P=0.005, 0.001, 0.003, <0.001, <0.001) and C-peptide 30 min (P=0.003), 60 min (P<0.001), 120 min (P=0.004), 180 min (P=0.038) ([Table 4]).

Furthermore, logistic regression analysis was performed to identify the risk factors for AN in obese patients, including FFA, BMI, age, TSH, UA, Leptin, TG, TC, Testosterone. Results demonstrated that increased UA (P<0.001) and increased Leptin (P=0.021) were independently correlated with AN. Testosterone was another independent risk factor in males only (P<0.001). In females, UA was the only independent risk factor (P=0.014) ([Table 5]).

Discussion

Obesity has become a worldwide public health problem. However, few studies have focused on the differences between obese patients with and without AN. In this study, we demonstrated that compared with OB, AN patients had more severe degrees of hyperinsulinemia, hyperuricemia, hyperleptindemia, and hypoandrogenisim in male patients. The data presented herein also provide the first evidence that UA and leptin were risk factors for the development of AN. We also provide evidence that low serum levels of testosterone may differentiate obese patients with AN from those without AN.

Previous study has demonstrated that AN is closely associated with insulin resistance [22], we presented that AN patients had high serum levels of fasting insulin, and hyperinsulinemia demonstrating high degrees of insulin resistance. Compared with OB, AN patients had higher serum levels of leptin. Our result is supported by Atwa’s study [5], which also reported higher serum leptin in obese AN patients. Study showed that leptin could stimulate the production of important growth factors [23] which may lead to induce proliferation of oral keratinocytes. Therefore, Elevated leptin levels may play a pathological role in the development of skin hyperpigmentation in AN. Stallmeyer [24] demonstrated that in leptin-deficient ob/ob mice, supplement leptin could improve re-epithelialization. They observed that the leptin receptor subtype ob/Rb was constitutively expressed in non-wounded skin while leptin was persist present at the wound site during healing. Takahashi [25] reported that leptin could promote cell proliferation and induce THF-α production by blood monocytes, also. In addition, leptin receptor was found in normal human keratinocyte (NHK) cell and Hut 102 cells in protein and mRNA. So leptin could combine with its receptor and promote cell proliferation which may lead to AN. The analysis of our study revealed leptin was positively correlated with insulin and C peptide, suggesting serum levels of leptin might be a key feature of hyperinsulinemia and insulin resistance. Leptin is an independent risk factor for AN, and high serum levels of leptin as symbol of AN in obese patients.

Many researches have already confirmed that hyperuricemia is closely associated with metabolic syndrome [26] [27], cardiovascular disease [28], and has regulatory effects on the metabolism of liver, adipose tissue and skeletal muscle [29]. In type 2 diabetes, effective control of uric acid could increase glomerular filtration rate (GFR) and protect kidney function [30]. However, no research has already focused on the relationship between UA and obesity related AN. In our study, compared with the OB group, AN patients showed higher degrees of hyperuricemia. Kleikamp [31] reported that an obese male patient had a history of hyperuricemia with thickening, coarseness and hyperpigmentation in the intertriginous areas of skin. This study showed that in most patients with diabetes, UA levels above normal were due to insulin resistance and hyperinsulinemia [32]. The process of AN is also related to insulin resistance. The present study showed that compared with OB patients, AN patients had higher levels of serum insulin at 0, 30, 60, and 120 min. It is possible that high levels of UA indicate the presence of AN due to insulin resistance. Multiple logistic-regression analysis demonstrated UA was an independent risk factor in both males and females for AN. This may have indications for treatment. For instance, obese patients with elevated UA may be at increased risk for developing AN and subsequently more severe insulin resistance. This group of patients likely warrants more aggressive and earlier initiation of treatment. Further studies are still needed to identify the underlying mechanism whereby UA leads to AN.

To our knowledge, no previous study has studied testosterone levels in AN patients. In the subgroup analysis for male patients, we found that AN patients had significantly lower serum levels of total testosterone than OB patients, and multiple logistic-regression analysis showed that lower serum testosterone were an independent risk factor of AN in male patients. However, the 2 groups showed no significant differences in other hormones including E2 and P indicating the specificity of testosterone. Studies showed that excess body weight in men is a factor associated with lower total testosterone levels [33] and lower total testosterone was an independent predictor of metabolic syndrome [34]. In type 2 diabetes patients with hypogonadotropic hypogonadism (HH), testosterone treatment could increased insulin sensitivity [35]. In obese young adults, it was demonstrated that free testosterone plasma levels were negatively associated with the intima-media thickness of the common carotid artery [36]. However, total testosterone includes free testosterone and sex hormone binding globulin (SHBG). Studies have shown that obesity was associated with lowered SHBG and may involve suppression of hepatic SHBG synthesis by elevated concentrations of insulin, but the mechanism has yet to be fully elucidated [37] [38]. Our study did not assess the individual contributions of free testosterone and SHBG, therefore further work will be needed to determine the effects of each in the development of AN.

There are several limitations to this study. Primarily, while we provide some data regarding the metabolic features of AN and the potential role of leptin, additional work will be needed to elucidate the underling mechanisms. Secondly, this study was limited because of the small number of patients. Therefore, we cannot infer causality from our results. Finally, our results might not be applied to other racial or age groups because the subjects enrolled in this study were Chinese adults.

Conclusions

Our study demonstrated that patient with AN have significantly higher levels of leptin compared with obese patients without AN. We also demonstrated that both UA and leptin levels are independently correlated with AN. In males, a low testosterone level was found to be a risk factor for AN. Our work provides a useful model for prediction of AN and for the selection of obese patients who need early radical intervention. Large, multicenter, randomized, double blind control studies are needed to confirm these findings and additional work is needed to understand the underlying mechanisms and signaling pathways involved.

Authors’ Contribution

Yueye Huang conceived of the study and wrote the manuscript. Jiaqi Chen, Xingchun Wang, Yan Li and Shezhen Yang participated the design of the study. Shen Qu organized the paper and approved the final version. All authors read and approved the final version.

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgements

This article was supported by the financial from the Shanghai Shenkang Prevention Prog of Disease (No. SHDC12012303). We thank Aaron Gusdon for the English editing.

• References

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• 3 Sinha S, Schwartz RA. Juvenile acanthosis nigricans. J Am Acad Dermatol 2007; 57: 502-508
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• 4 Kobaissi HA, Weigensberg MJ, Ball GD et al. Relation between acanthosis nigricans and insulin sensitivity in overweight Hispanic children at risk for type 2 diabetes. Diabetes Care 2004; 27: 1412-1416
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• 5 Atwa M, Emara A, Balata M et al. Serum leptin, adiponectin, and resistin among adult patients with acanthosis nigricans: correlations with insulin resistance and risk factors for cardiovascular disease. Int J Dermatol 2014; 53: e410-e420
  CrossrefPubMedGoogle Scholar
• 6 Koerner A, Kratzsch J, Kiess W. Adipocytokines: leptin – the classical, resistin – the controversical, adiponectin – the promising, and more to come. Best Pract Res Clin Endocrinol Metab 2005; 19: 525-546
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• 7 Zhang F, Chen Y, Heiman M et al. Leptin: structure, function and biology. Vitam Horm 2005; 71: 345-372
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• 9 Zhou Y, Rui L. Leptin signaling and leptin resistance. Front Med 2013; 7: 207-222
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• 11 Ames BN, Cathcart R, Schwiers E et al. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 1981; 78: 6858-6862
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• 12 Sautin YY, Johnson RJ. Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids 2008; 27: 608-619
  CrossrefPubMedGoogle Scholar
• 13 Kodama S, Saito K, Yachi Y et al. Association between serum uric acid and development of type 2 diabetes. Diabetes Care 2009; 32: 1737-1742
  CrossrefPubMedGoogle Scholar
• 14 Khosla UM, Zharikov S, Finch JL et al. Hyperuricemia induces endothelial dysfunction. Kidney Int 2005; 67: 1739-1742
  CrossrefPubMedGoogle Scholar
• 15 Chuengsamarn S, Rattanamongkolgul S, Jirawatnotai S. Association between serum uric acid level and microalbuminuria to chronic vascular complications in Thai patients with type 2 diabetes. J Diabetes Complications 2014; 28: 124-129
  CrossrefPubMedGoogle Scholar
• 16 Xia J, Wang Z, Zhang F. Association between Related Purine Metabolites and Diabetic Retinopathy in Type 2 Diabetic Patients. Int J Endocrinol 2014; 2014 651050
  PubMedGoogle Scholar
• 17 Li L, Yang C, Zhao Y et al. Is hyperuricemia an independent risk factor for new-onset chronic kidney disease?: A systematic review and meta-analysis based on observational cohort studies. BMC Nephrol 2014; 15: 122
  CrossrefPubMedGoogle Scholar
• 18 Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008; 359: 1811-1821
  CrossrefPubMedGoogle Scholar
• 19 Daskalopoulou SS, Athyros VG, Elisaf M et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004; 66: 1714-1715
  PubMedGoogle Scholar
• 20 Burke JP, Hale DE, Hazuda HP et al. A quantitative scale of acanthosis nigricans. Diabetes Care 1999; 22: 1655-1659
  CrossrefPubMedGoogle Scholar
• 21 Bonora E, Targher G, Alberiche M et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 2000; 23: 57-63
  CrossrefPubMedGoogle Scholar
• 22 Hermanns-Le T, Scheen A, Pierard GE. Acanthosis nigricans associated with insulin resistance: pathophysiology and management. Am J Clin Dermatol 2004; 5: 199-203
  CrossrefPubMedGoogle Scholar
• 23 Groschl M, Topf HG, Kratzsch J et al. Salivary leptin induces increased expression of growth factors in oral keratinocytes. J Mol Endocrinol 2005; 34: 353-366
  CrossrefPubMedGoogle Scholar
• 24 Stallmeyer B, Kampfer H, Podda M et al. A novel keratinocyte mitogen: regulation of leptin and its functional receptor in skin repair. J Invest Dermatol 2001; 117: 98-105
  CrossrefPubMedGoogle Scholar
• 25 Takahashi H, Honma M, Ishida-Yamamoto A et al. Adiponectin and leptin modulate cell proliferation and cytokine secretion of normal human keratinocytes and T lymphocytes. J Dermatol Sci 2010; 59: 143-145
  CrossrefPubMedGoogle Scholar
• 26 Wei CY, Sun CC, Wei JC et al. Association between Hyperuricemia and Metabolic Syndrome: An Epidemiological Study of a Labor Force Population in Taiwan. Biomed Res Int 2015; 2015 369179
  PubMedGoogle Scholar
• 27 Johnson RJ. Why focus on uric acid?. Curr Med Res Opin 2015; 31 (Suppl. 02) 3-7
  CrossrefPubMedGoogle Scholar
• 28 Su P, Hong L, Zhao Y et al. Relationship Between Hyperuricemia and Cardiovascular Disease Risk Factors in a Chinese Population: A Cross-Sectional Study. Med Sci Monit 2015; 21: 2707-2717
  CrossrefPubMedGoogle Scholar
• 29 Lima WG, Martins-Santos ME, Chaves VE. Uric acid as a modulator of glucose and lipid metabolism. Biochimie 2015; 116: 17-23
  CrossrefPubMedGoogle Scholar
• 30 Liu P, Chen Y, Wang B et al. Allopurinol treatment improves renal function in patients with type 2 diabetes and asymptomatic hyperuricemia: 3-year randomized parallel-controlled study. Clin Endocrinol (Oxf) 2015; 83: 475-482
  CrossrefPubMedGoogle Scholar
• 31 Kleikamp S, Bohm M, Frosch P et al. Acanthosis nigricans, papillomatosis mucosae and “tripe palms” in a patient with metastasized gastric carcinoma. Dtsch Med Wochenschr 2006; 131: 1209-1213
  Article in Thieme ConnectPubMedGoogle Scholar
• 32 Bo S, Cavallo-Perin P, Gentile L et al. Hypouricemia and hyperuricemia in type 2 diabetes: two different phenotypes. Eur J Clin Invest 2001; 31: 318-321
  CrossrefPubMedGoogle Scholar
• 33 Rotter I, Kosik-Bogacka D, Dolegowska B et al. Analysis of relationships between the concentrations of total testosterone and dehydroepiandrosterone sulfate and the occurrence of selected metabolic disorders in aging men. Aging Male 2015; 18: 249-255
  CrossrefPubMedGoogle Scholar
• 34 Wickramatilake CM, Mohideen MR, Pathirana C. Association of metabolic syndrome with testosterone and inflammation in men. Ann Endocrinol (Paris) 2015; 76: 260-263
  CrossrefPubMedGoogle Scholar
• 35 Dhindsa S, Ghanim H, Batra M et al. Insulin Resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes Care 2016; 39: 82-91
  CrossrefPubMedGoogle Scholar
• 36 De Pergola G, Pannacciulli N, Ciccone M et al. Free testosterone plasma levels are negatively associated with the intima-media thickness of the common carotid artery in overweight and obese glucose-tolerant young adult men. Int J Obes Relat Metab Disord 2003; 27: 803-807
  CrossrefPubMedGoogle Scholar
• 37 Cooper LA, Page ST, Amory JK et al. The association of obesity with sex hormone-binding globulin is stronger than the association with ageing – implications for the interpretation of total testosterone measurements. Clin Endocrinol (Oxf) 2015; 83: 828-833
  CrossrefPubMedGoogle Scholar
• 38 Peter A, Kantartzis K, Machann J et al. Relationships of circulating sex hormone-binding globulin with metabolic traits in humans. Diabetes 2010; 59: 3167-3173
  CrossrefPubMedGoogle Scholar

Correspondence

• References

• 1 Ng M, Fleming T, Robinson M et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384: 766-781
  CrossrefPubMedGoogle Scholar
• 2 Jones LH, Ficca M. Is Acanthosis Nigricans a reliable indicator for risk of type 2 diabetes?. J Sch Nurs 2007; 23: 247-251
  CrossrefPubMedGoogle Scholar
• 3 Sinha S, Schwartz RA. Juvenile acanthosis nigricans. J Am Acad Dermatol 2007; 57: 502-508
  CrossrefPubMedGoogle Scholar
• 4 Kobaissi HA, Weigensberg MJ, Ball GD et al. Relation between acanthosis nigricans and insulin sensitivity in overweight Hispanic children at risk for type 2 diabetes. Diabetes Care 2004; 27: 1412-1416
  CrossrefPubMedGoogle Scholar
• 5 Atwa M, Emara A, Balata M et al. Serum leptin, adiponectin, and resistin among adult patients with acanthosis nigricans: correlations with insulin resistance and risk factors for cardiovascular disease. Int J Dermatol 2014; 53: e410-e420
  CrossrefPubMedGoogle Scholar
• 6 Koerner A, Kratzsch J, Kiess W. Adipocytokines: leptin – the classical, resistin – the controversical, adiponectin – the promising, and more to come. Best Pract Res Clin Endocrinol Metab 2005; 19: 525-546
  CrossrefPubMedGoogle Scholar
• 7 Zhang F, Chen Y, Heiman M et al. Leptin: structure, function and biology. Vitam Horm 2005; 71: 345-372
  PubMedGoogle Scholar
• 8 Polyzos SA, Kountouras J, Mantzoros CS. Leptin in nonalcoholic fatty liver disease: a narrative review. Metabolism 2015; 64: 60-78
  CrossrefPubMedGoogle Scholar
• 9 Zhou Y, Rui L. Leptin signaling and leptin resistance. Front Med 2013; 7: 207-222
  CrossrefPubMedGoogle Scholar
• 10 Allison MA, Lx JH, Morgan C et al. Higher leptin is associated with hypertension: the Multi-Ethnic Study of Atherosclerosis. J Hum Hypertens 2013; 27: 617-622
  CrossrefPubMedGoogle Scholar
• 11 Ames BN, Cathcart R, Schwiers E et al. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 1981; 78: 6858-6862
  CrossrefPubMedGoogle Scholar
• 12 Sautin YY, Johnson RJ. Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids 2008; 27: 608-619
  CrossrefPubMedGoogle Scholar
• 13 Kodama S, Saito K, Yachi Y et al. Association between serum uric acid and development of type 2 diabetes. Diabetes Care 2009; 32: 1737-1742
  CrossrefPubMedGoogle Scholar
• 14 Khosla UM, Zharikov S, Finch JL et al. Hyperuricemia induces endothelial dysfunction. Kidney Int 2005; 67: 1739-1742
  CrossrefPubMedGoogle Scholar
• 15 Chuengsamarn S, Rattanamongkolgul S, Jirawatnotai S. Association between serum uric acid level and microalbuminuria to chronic vascular complications in Thai patients with type 2 diabetes. J Diabetes Complications 2014; 28: 124-129
  CrossrefPubMedGoogle Scholar
• 16 Xia J, Wang Z, Zhang F. Association between Related Purine Metabolites and Diabetic Retinopathy in Type 2 Diabetic Patients. Int J Endocrinol 2014; 2014 651050
  PubMedGoogle Scholar
• 17 Li L, Yang C, Zhao Y et al. Is hyperuricemia an independent risk factor for new-onset chronic kidney disease?: A systematic review and meta-analysis based on observational cohort studies. BMC Nephrol 2014; 15: 122
  CrossrefPubMedGoogle Scholar
• 18 Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008; 359: 1811-1821
  CrossrefPubMedGoogle Scholar
• 19 Daskalopoulou SS, Athyros VG, Elisaf M et al. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004; 66: 1714-1715
  PubMedGoogle Scholar
• 20 Burke JP, Hale DE, Hazuda HP et al. A quantitative scale of acanthosis nigricans. Diabetes Care 1999; 22: 1655-1659
  CrossrefPubMedGoogle Scholar
• 21 Bonora E, Targher G, Alberiche M et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 2000; 23: 57-63
  CrossrefPubMedGoogle Scholar
• 22 Hermanns-Le T, Scheen A, Pierard GE. Acanthosis nigricans associated with insulin resistance: pathophysiology and management. Am J Clin Dermatol 2004; 5: 199-203
  CrossrefPubMedGoogle Scholar
• 23 Groschl M, Topf HG, Kratzsch J et al. Salivary leptin induces increased expression of growth factors in oral keratinocytes. J Mol Endocrinol 2005; 34: 353-366
  CrossrefPubMedGoogle Scholar
• 24 Stallmeyer B, Kampfer H, Podda M et al. A novel keratinocyte mitogen: regulation of leptin and its functional receptor in skin repair. J Invest Dermatol 2001; 117: 98-105
  CrossrefPubMedGoogle Scholar
• 25 Takahashi H, Honma M, Ishida-Yamamoto A et al. Adiponectin and leptin modulate cell proliferation and cytokine secretion of normal human keratinocytes and T lymphocytes. J Dermatol Sci 2010; 59: 143-145
  CrossrefPubMedGoogle Scholar
• 26 Wei CY, Sun CC, Wei JC et al. Association between Hyperuricemia and Metabolic Syndrome: An Epidemiological Study of a Labor Force Population in Taiwan. Biomed Res Int 2015; 2015 369179
  PubMedGoogle Scholar
• 27 Johnson RJ. Why focus on uric acid?. Curr Med Res Opin 2015; 31 (Suppl. 02) 3-7
  CrossrefPubMedGoogle Scholar
• 28 Su P, Hong L, Zhao Y et al. Relationship Between Hyperuricemia and Cardiovascular Disease Risk Factors in a Chinese Population: A Cross-Sectional Study. Med Sci Monit 2015; 21: 2707-2717
  CrossrefPubMedGoogle Scholar
• 29 Lima WG, Martins-Santos ME, Chaves VE. Uric acid as a modulator of glucose and lipid metabolism. Biochimie 2015; 116: 17-23
  CrossrefPubMedGoogle Scholar
• 30 Liu P, Chen Y, Wang B et al. Allopurinol treatment improves renal function in patients with type 2 diabetes and asymptomatic hyperuricemia: 3-year randomized parallel-controlled study. Clin Endocrinol (Oxf) 2015; 83: 475-482
  CrossrefPubMedGoogle Scholar
• 31 Kleikamp S, Bohm M, Frosch P et al. Acanthosis nigricans, papillomatosis mucosae and “tripe palms” in a patient with metastasized gastric carcinoma. Dtsch Med Wochenschr 2006; 131: 1209-1213
  Article in Thieme ConnectPubMedGoogle Scholar
• 32 Bo S, Cavallo-Perin P, Gentile L et al. Hypouricemia and hyperuricemia in type 2 diabetes: two different phenotypes. Eur J Clin Invest 2001; 31: 318-321
  CrossrefPubMedGoogle Scholar
• 33 Rotter I, Kosik-Bogacka D, Dolegowska B et al. Analysis of relationships between the concentrations of total testosterone and dehydroepiandrosterone sulfate and the occurrence of selected metabolic disorders in aging men. Aging Male 2015; 18: 249-255
  CrossrefPubMedGoogle Scholar
• 34 Wickramatilake CM, Mohideen MR, Pathirana C. Association of metabolic syndrome with testosterone and inflammation in men. Ann Endocrinol (Paris) 2015; 76: 260-263
  CrossrefPubMedGoogle Scholar
• 35 Dhindsa S, Ghanim H, Batra M et al. Insulin Resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes Care 2016; 39: 82-91
  CrossrefPubMedGoogle Scholar
• 36 De Pergola G, Pannacciulli N, Ciccone M et al. Free testosterone plasma levels are negatively associated with the intima-media thickness of the common carotid artery in overweight and obese glucose-tolerant young adult men. Int J Obes Relat Metab Disord 2003; 27: 803-807
  CrossrefPubMedGoogle Scholar
• 37 Cooper LA, Page ST, Amory JK et al. The association of obesity with sex hormone-binding globulin is stronger than the association with ageing – implications for the interpretation of total testosterone measurements. Clin Endocrinol (Oxf) 2015; 83: 828-833
  CrossrefPubMedGoogle Scholar
• 38 Peter A, Kantartzis K, Machann J et al. Relationships of circulating sex hormone-binding globulin with metabolic traits in humans. Diabetes 2010; 59: 3167-3173
  CrossrefPubMedGoogle Scholar