Endokrynologia 1 2013-8

Prace oryginalne/Original papers


Relationships between adiponectin, sex hormone binding globulin and insulin resistance in hyperthyroid Graves’ disease women

Powiązania pomiędzy adiponektyną, białkiem wiążącym hormony płciowe i opornością insulinową w nadczynności tarczycy u kobiet z chorobą Gravesa

Lucyna Siemińska1, Wanda Foltyn1, Joanna Głogowska-Szeląg1, Dariusz Kajdaniuk1, Bogdan Marek1, Mariusz Nowak1, Krzysztof Walczak2, Beata Kos-Kudła1

1Department of Pathophysiology and Endocrinology, Medical University of Silesia, Zabrze, Poland2Regional Railway Hospital, Katowice, Poland


Lucyna Siemińska M.D., Ph.D., Department of Pathophysiology and Endocrinology, Medical University of Silesia, 41–800 Zabrze,pl. Traugutta 2, tel./fax: +48 32 278 61 26, e-mail: lusiem@poczta.onet.pl


Introduction: Adiponectin and sex hormone binding globulin (SHBG) play a role in glucose metabolism. Hyperthyroidism has an impact on carbohydrate metabolism and could affect insulin resistance. The aim of this study was to assess the associations between insulin resis­tance, adiponectin and SHBG among hyperthyroid Graves` disease (GD) women.

Material and methods: The study was undertaken in 60 women with hyperthyroidism in the course of GD; 32 healthy women matched by BMI and age formed the control group. The concentrations of: free thyroxine (fT4), free triiodothyronine (fT3), thyroid-stimulating hormone (TSH), SHBG, insulin, adiponectin and glucose were measured, and the homeostasis model assessment (HOMA-I) was calculated.

Results: Compared to euthyroid subjects, hyperthyroid GD women had elevated glucose, fT4, fT3, adiponectin and SHBG concentrations, but there were no differences in HOMA-I. When we explored the relations between adiponectin as well as SHBG with glucose and HOMA-I, we observed that HOMA-I was associated with adiponectin and SHBG only in the control group, and in hyperthyroidism there were no such connections. We found positive associations between adiponectin, SHBG, fT4 and fT3 in the GD group.

Conclusions: Elevated concentrations of adiponectin and SHBG were observed in hyperthyroidism but they were not related to insulin resistance. (Endokrynol Pol 2013; 64 (1): 26–29)

Key words: hyperthyroidism, insulin resistance, adiponectin, SHBG


Wstęp: Adiponektyna i białko wiążące hormony płciowe (SHBG) odgrywają rolę w metabolizmie glukozy. W nadczynności tarczycy często występują zaburzenia gospodarki węglowodanowej i oporność insulinowa. Celem pracy była próba oceny powiązań pomiędzy adiponektyną, SHBG i opornością insulinową u kobiet z nadczynnością tarczycy w przebiegu choroby Gravesa.

Materiał i metody: Badanie przeprowadzono wśród 60 kobiet z nadczynnością tarczycy w przebiegu choroby Gravesa. 32 zdrowe kobiety stanowiły grupę kontrolną. Grupy nie różniły się między sobą pod względem wieku i BMI. Oceniano stężenie: wolnej tyroksyny (fT4), wolnej trijodotyroniny (fT3), TSH, SHBG, insuliny, adiponektyny i glukozy. Oporność insulinową oceniano jako wskaźnik HOMA-I.

Wyniki: Porównując z grupą kontrolną, kobiety z nadczynnością miały wyższe stężenie fT4, fT3, SHBG, adiponektyny, glukozy, natomiast nie stwierdzono różnic we wskaźniku HOMA-I. Gdy oceniano powiązania pomiędzy adiponektyną, SHBG oraz HOMA-I i glukozą, stwierdzono korelacje tylko w grupie kontrolnej, natomiast w grupie badanej te zależności nie występowały. Wykryto powiązania pomiędzy adiponektyną, SHBG, fT4 i fT3 w grupie kobiet z tyreotoksykozą.

Wnioski: W nadczynności tarczycy występują podwyższone stężenia adiponektyny i SHBG, ale nie wpływa to na rozwój oporności insulinowej. (Endokrynol Pol 2013; 64 (1): 26–29)

Słowa kluczowe: nadczynność tarczycy, oporność insulinowa, adiponektyna, SHBG


Impaired fasting glucose and impaired glucose tolerance often develop in hyperthyroidism. In patients with diabetes, the progress of diabetes is usually worsening and unstable, due to a variety of mechanisms. Thyroid hormones act antagonistically to insulin, mainly within the liver level. Gluconeogenesis and glycogenolysis increase. The expression of glucose transporter 2 (GLUT-2) in the hepatocytes and the cellular glucose transport intensifies. In the digestive tract, glucose resorption increases, secondary to the intensified expression of the sodium/glucose transporter that is located on the surface of the enterocytes. At the same time, in the course of hormone sensitive lipase (HSL) dependent lipolysis, substantial quantities of free fatty acids are released in adipose tissue, which may contribute to the develo­pment of peripheral insulin resistance [1]. Elevated homeostasis model assessment of insulin resistance index (HOMA-I) has been reported in hyperthyroidism in some [2] but not in all studies [3]. The excess of thyroid hormones significantly affects adipocyte function, mainly lipoprotein metabolism, as well as adipocytokines secretion [4, 5]. Reduced adiponectin serum level has been shown to be a sensitive indicator of insulin resistance [6, 7]. However, several researchers have described a higher concentration of adiponectin in the hyperthyroid stage compared to healthy persons [5, 8, 9]. Another marker linked to insulin resistance is the concentration of the sex hormone binding globulin (SHBG) [10]. Insulin resistance is connected to a reduced concentration of SHBG [10], but in hyperthyroidism the secretion of SHBG increases [11]. The contribution of adiponectin and SHBG in the pathogenesis of deregulations in the carbohydrate metabolism in the course of hyperthyroidism is not known.

The aim of this study was to attempt to evaluate the connections between insulin resistance and SHBG as well as adiponectin in hyperthyroidism.

Material and methods

The study was undertaken in 60 women with hyperthyroidism in the course of Graves` disease (GD); 32 healthy women formed the control group. The groups did not differ in terms of age and body mass index (BMI). GD was diagnosed on the basis of typical clinical picture, ultrasonographic image, and increased level of TSH receptor antibodies (TRAb) and thyroid peroxidase antibodies (TPO-Abs). The patients were evaluated at the time of diagnosis. The concentrations of free thyroid hormones, i.e. free thyroxine (fT4), free triiodothyronine (fT3) and thyroid-stimulating hormone (TSH) were estimated by the radioimmunology method (ZenTech S.A.). The concentrations of SHBG and insulin were measured using RIA commercial kits (DSL), adiponectin was measured by RIA (Linco Research), and glucose with the use of Roche Diagnostic reagent. The insulin resistance index assessed by the homeostasis model assessment was calculated using the formula: HOMA-I = concentration of glucose in blood serum (mg/dL)/ 18.1 × concentration of insulin (ulU/mL)/22.5 [12]. The study was approved by the Bioethics Committee of the Medical University of Silesia.


The concentrations of free hormones were significantly higher, and the concentration of TSH lower, in hyperthyroidism than in the control group. The glucose concentration was higher in patients with GD compared to the control group, but there weren’t any differences between the groups in terms of HOMA-I (Table I). In this study we observed significantly higher concentrations of adiponectin and SHBG in the hyperthyroid group compared to the control group (Table I). We showed a significant relationship between the concentration of adiponectin and fT4, as well as between adiponectin and fT3 in the hyperthyroid group. We also found positive correlations between the concentrations of SHBG and the concentrations of fT3 and fT4 in the hyperthyroidism group (Table II). These correlations were not present in the control group.

Table I. Clinical and biochemical characteristics of the hyperthyroid and control groups, *p < 0.001 tested v. control group

Tabela I. Porównanie parametrów klinicznych i biochemicznych pomiędzy grupą z nadczynnością tarczycy i grupą kontrolną, *p < 0.001 grupa badana v. grupa kontrolna

Hyperthyroid group

Control group




Age (years)

45.8 ± 7.7

49.2 ± 7.3

BMI [kg/m2]

24.6 ± 2.6

24.7 ± 2.6

Glucose [mg/dL]

91.3 ± 4.6*

87.0 ± 5.6

Adiponectin [ug/mL]

20.16 ± 5.94*

14.91 ± 4.95

SHBG [nmol/L]

115.7 ± 35.9*

86.4 ± 22.5


1.4 (0.9; 1.5)

1.2 [0.8; 1.6]

TSH [mIU/mL]

0.01 ± 0.02*

1.48 ± 0.85

fT4 [ng/dL]

2.53 ± 0.54*

1.13 ± 0.32

fT3 [pg/mL]

7.13 ± 3.25*

2.55 ± 1.21

Normally distributed data is given as mean SD. Skewed data is given as median plus [25;75] percentiles. The significance tests used are the Mann-Whitney test for normally distributed variables, and unpaired t test for normally distributed variables

Table II. Spearman`s coefficients of the relationships between biochemical parameters in the hyperthyroid group

Tabela II. Współczynniki korelacji R Spearmana pomiędzy ocenianymi parametrami w grupie badanej

Adiponectin and fT4

R Spearman = 0.33, p < 0.001

Adiponectin and fT3

R Spearman = 0.28, p < 0.001

Adiponectin and SHBG

R Spearman = 0.33, p < 0.01

SHBG and fT4

R Spearman = 0.35, p < 0.001

SHBG and fT3

R Spearman = 0.30, p < 0.001

In both the hyperthyroid and control groups, adiponectin correlated positively with SHBG concentrations. HOMA-I was connected with BMI, SHBG and adiponectin only in healthy women but not in hyperthyroid Graves patients.


Hyperthyroidism has an impact on carbohydrate metabolism and could affect insulin resistance. The implicated mechanisms are complex and in part unclear. Hyperglycaemia results from increased carbohydrate absorption, increased gluconeogenesis, and reduced hepatic glycogen synthesis. Hyperthyroidism can also cause a decrease in tissue reactivity for physiological insulin level, which leads to glucose and lipid metabolism dysregulation. Resistance at the molecular level is due to defects of the insulin induced stimulation cascade [13]. In this study, we observed increased fasting glucose in hyperthyroid patients, but when we evaluated insulin resistance by HOMA-I, which we determined on the basis of glucose and insulin concentration, we did not found any differences between hyperthyroid women compared to a control group. However, hyperthyroidism can lead to a reduction of BMI which promotes insulin sensitivity. Therefore insulin resistance is mediated by different confusing factors.

Adipose tissue releases a number of bioactive adipokines such as adiponectin. Serum adiponectin is inversely related to the adipose mass and intensifies insulin sensitivity. Researchers have proved that low adiponectin levels determine the grade of insulin resistance independent from fat tissue mass [7]. The globulin directly corrects the insulin signal transfer and reduces the glucose concentration without influencing insulin secretion. In skeletal muscles, through AMP kinase it intensifies the expression of GLUT-4 and the glucose uptake. Under the influence of adiponectin, the activity of enzymes responsible for gluconeogenesis decreases [6].

Excess of thyroid hormones in hyperthyroidism leads to lipolysis, a reduction of fat mass, and weight loss. Since adipose tissue is reduced in hyperthyroid subjects, secretion of adiponectin could be dysregulated. Little is known about adiponectin production in hyperthyroidism and the limited information about this issue is demonstrated by different results. In human studies, the excess of thyroid hormones have been connected with similar [4, 14] or elevated serum adiponectin levels [5, 8, 9]. In the study by Hsieh et al., the treatment of thyrotoxicosis was followed by a significant decline of serum adiponectin [15]. In the present study, higher levels of adiponectin were found in hyperthyroid GD women compared to the control group and adiponectin was not correlated with HOMA-I in hyperthyroidism. This finding does not support a role of adiponectin as a factor mediated in disturbances in carbohydrate metabolism in thyrotoxicosis.

The mechanism that binds the adiponectin production in respect of the hyperfunction severity grade is not known. In our study, adiponectin concentrations correlated positively with the concentrations of free thyroid hormones, which is compatible with reports by other researchers [5, 8, 9, 15]. It is possible that elevated adiponectin levels might be a result of thyroid hormones stimulation on peroxisome proliferator activated receptor (PPAR) and sterol-regulatory-element-binding protein (SREBP) signaling [16, 17]. Adiponectin is produced by small, differentiating fat cells, and the adiponectin gene expression during the preadipocyte maturation increases by as much as 100 times. The transcription factors: SREBP-1c, CCAAT/enhancer-binding protein (C/EBP), and PPAR stimulate adiponectin gene expression [16]. The secretion also intensifies under the influence of insulin, which stimulates SREBP-1c. In hyperthyroid subjects, increased secretion of insulin has been demonstrated [1]. Glucocorticosteroids, catecholamines and inflammatory cytokines, such as interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha), are inhibiting factors [18]. PPAR gamma plays the main role in inducing the adiponectin gene, and the nuclear factor agonists increase adiponectin blood concentration [19]. PPAR binds with the retinoid X receptor (RXR), and the formed dimer binds to DNA within the region of adiponectin gene promoter (PPRE, PPAR response element), which leads to gene activation [16].

Furthermore, in the present study, adiponectin correlated positively with SHBG. The connections were independent from BMI and thyroid function. Those relations have been seen before [20, 21], although their nature is not known. Gannage-Yares et al. suggested that adiponectin could be connected to the production of SHBG through hepatocytes [22]. SHBG is a glycoprotein coded by a gene located on chromosome 17. It is produced by hepatocytes under the control of different endocrine and metabolic factors. Oestradiol stimulates its synthesis, but insulin and testosterone inhibits it [23]. GH and somatomedin are important negative determinants of SHBG levels, and thyroid hormones have a strongly positive effect on the production of SHBG. Increased production of SHBG in hyperthyroidism has been seen previously [11], and was confirmed in our study. We also observed the positive correlations between SHBG and thyroid hormones. Selva et al. have demonstrated that thyroid hormones increase hepatic SHBG production by increasing expression of hepatocyte nuclear factor-4 alpha (HNF 4-α) [24].

Until recently, it has been believed that SHBG synthesis in the liver was directly regulated by insulinaemia. However, Selva et al. have questioned the pivotal role of insulin, and suggested that the increase of HNF 4- expression leads to higher SHBG production [25].

The important factor affected SHBG serum levels is insulin resistance. Low serum SHBG concentrations have been shown to predict the occurrence of insulin resistance in women [26]. However, in this study we did not observe relationships between SHBG concentrations and HOMA-I levels among hyperthyroid women. These observations suggest that insulin sensitivity is not mediated by SHBG in the hyperthyroid stage.


There are no relationships between insulin resistance, SHBG and adiponectin in hyperthyroidism. Elevated SHBG and adiponectin concentrations reflect the degree of thyroid hyperfunction.


  1. 1. Mitrou P, Raptis SA, Dimitriadis G. Insulin action in hyperthyroidism: a focus on muscle and adipose tissue. Endocr Rev 2010; 31: 663–679.
  2. 2. Maratou E, Hadjidakis D, Peppa M et al. Studies of insulin resistance in patients with clinical and subclinical hyperthyroidism. Eur J Endocrinol 2010; 163: 625–630.
  3. 3. Owecki M, Nikisch E, Sowiński J. Insulin resistance assessed with HOMA-IR in hyperthyroid patients. Pol Merkur Lekarski 2005; 113: 617–20.
  4. 4. Iglesias P, Alvarez Fidalgo P, Codoceo R et al. Serum concentrations of adipocytokines in patients with hyperthyroidism and hypothyroidism before and after control thyroid function. Clin Endocrinol 2003; 59: 621-9.
  5. 5. Yaturu S, Prado S, Grimes SR. Changes in adipocyte hormones leptin, resistin,, and adiponectin in thyroid dysfunction. J Cell Biochem 2004; 93: 491–496.
  6. 6. Lihn AS, Pedersen SB, Richelsen B. Adiponectin: action, regulation and association to insulin sensitivity. Obes Rev 2005; 6: 13–21.
  7. 7. Weyer C, Funahashi T, Tanaka S et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001; 86: 1930–1935.
  8. 8. Yu H, Yang Y, Zhang MX et al. Thyroid status influence on adiponectin, acylation stimulating protein (ASP) and complement C3 in hyperthyroid and hypothyroid subjects. Nutr Metab (Lond) 2006; 3: 13.
  9. 9. Saito T, Kawano T, Saito T et al. Elevation of serum adiponectin levels in Basedow disease. Metabolism 2005; 5: 1461–1466.
  10. 10. Onat A, Hergenç G, Karabulut A et al. Serum sex hormone-binding globulin, a determinant of cardiometabolic disorders independent of abdominal obesity and insulin resistance in elderly men and women. Metabolism Clin Exper 2007; 56: 1356–1362.
  11. 11. Brenta G, Schnitman M, Gurfinkiel M et al. Variations of sex hormone-binding globulin in thyroid dysfunction. Thyroid 1999; 9: 273–277.
  12. 12. 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.
  13. 13. Tatoń J, Czech A, Piątkiewicz P. Insulin as the main regulator of cellular glucose utilization — aetiological aspects of insulin resistance. Endokrynol Pol 2010; 61: 388–394.
  14. 14. Chu CH, Lam HC, Lee JK et al. Hyperthyroidism-associated insulin resistance is not mediated by adiponectin levels. J Thyroid Res 2011, doi:10.4061/2011/194721
  15. 15. Hsieh CJ, Wang PW. Serum concentrations of adiponectin in patients with hyperthyroidism before and after control of thyroid function. Endocr J 2008; 55: 48994.
  16. 16. Iwaki M, Matsuda M, Maeda N et al. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 2003; 52: 1655–1663.
  17. 17. Seo JB, Moon HM, Noh MJ et al. Adipocyte determination- and differentiation-dependent factor 1/sterol regulatory element-binding protein 1c regulates mouse adiponectin expression. J Biol Chem 2004; 279: 22108–22117.
  18. 18. Bruun JM, Lihn AS, Verdich C et al. Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab 2003; 285: E527–533.
  19. 19. Yang WS, Jeng CY, Wu TJ et al. Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 2002; 25: 376–380.
  20. 20. Sieminska L, Marek B, Kos-Kudla B et al. Serum adiponectin in women with polycystic ovarian syndrome and its relation to clinical, metabolic and endocrine parameters. Journal of Endocrinological Investigation 2004; 27: 528–534.
  21. 21. Wu AH, Yu MC, Stanczyk FZ et al. Anthropometric, dietary, and hormonal correlates of serum adiponectin in Asian American women. Nutr Cancer 2011; 63: 549–557.
  22. 22. Gannagé-Yared MH, Khalife S, Semaan M et al. Serum adiponectin and leptin levels in relation to the metabolic syndrome, androgenic profile and somatotropic axis in healthy non-diabetic elderly men. Eur J Endocrinology 2006; 155:167–176.
  23. 23. Loukovaara M, Carson M, Adlercreutz H. Regulation of production and secretion of sex hormone-binding globulin in HepG2 cell cultures by hormones and growth factors. J Clin Endocrinol Metab 1995; 80: 160–164.
  24. 24. Selva DM, Hammond GL. Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4alpha. J Mol Endocrinol 2009; 43: 1927.
  25. 25. Selva DM, Hogeveen KN, Innis SM et al. Monosaccharid-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. J Clin Invest 2007; 117: 3979–3987.
  26. 26. Akin F, Bastemir M, Alkis E et al. SHBG levels correlate with insulin resistance in postmenopausal women. Eur J Intern Med 2009; 20: 162–167.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

Via MedicaWydawcą serwisu jest  "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl