Abstract
Objective
To elucidate the link between TSH and obesity, the relationship between TSH and adipocytokines were previously studied. Animal studies demonstrated a possible relationship between vaspin levels and thyroid functions. In this study, we aimed to investigate vaspin levels in hypothyroid states and its relationship with insulin resistance parameters in humans.
Design
Prospective observational study.
Methods
We enrolled 27 overt hypothyroid, 33 subclinical hypothyroid and 41 euthyroid patients. We measured the body mass index (BMI), fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance index (HOMA-IR), lipid profile, TSH, free triiodothyronine, free thyroxine and vaspin levels. The change in vaspin levels in 12 overt hypothyroid patients after establishment of euthyroidism was analysed.
Results
All groups were age-matched. Overt hypothyroid group had higher BMI values (P<0.05) than other groups. No significant difference was observed in insulin levels and HOMA-IR among the groups (P>0.05). Adjusted vaspin levels for BMI and age were similar among the groups. Mean vaspin levels in overt, subclinical and euthyroid patients were 1.20±1.17, 1.48±0.93 and 0.95±0.75 ng/ml respectively (P>0.05). There was no significant association between vaspin levels and BMI, fasting glucose, insulin and HOMA-IR (P>0.05). Establishing euthyroidism in hypothyroid patients did not result in a significant change in vaspin levels (before and after treatment, 1.35±1.06 and 1.25±0.68 ng/ml, respectively; P>0.05).
Conclusion
We herein present novel data indicating vaspin levels are neither altered in overt and subclinical hypothyroidism nor have a relationship with features of insulin resistance in hypothyroid patients.
Introduction
Adipose tissue acts as an endocrine organ and plays a great role in the pathogenesis of insulin resistance, diabetes and atherosclerosis by means of adipocyte-derived factors (adipocytokines). It is known that visceral adipose tissue (VAT) carries a greater metabolic risk than s.c. adipose tissue. Recently, Hida et al. (1) identified a novel insulin-sensitising adipocytokine called VAT-derived serine protease inhibitor (vaspin) from the VAT of obese, diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Vaspin was found to be a member of the serine protease inhibitor family (serpins). They reported that administration of vaspin to OLETF rats caused improvement in glucose tolerance and insulin sensitivity (1). Also, recent studies have documented positive association between vaspin gene expression in human adipose tissue and serum vaspin levels with obesity and type 2 diabetes (2, 3, 4).
Hypothyroidism has been associated with hypertension, dyslipidaemia, metabolic syndrome and increased cardiovascular risk. Insulin resistance plays major role in the development of metabolic syndrome. The data about the relationship between insulin resistance and hypothyroidism is still controversial. Some authors suggest that elevated TSH as a metabolic adaptation to obesity while others suggest that elevated TSH is associated with insulin resistance, dyslipidaemia and subclinical inflammation resulting in an increased risk of coronary artery disease. Even slightly higher TSH within the normal reference range has been linked to higher body mass index (BMI), dyslipidaemia and fatal coronary artery disease. Decreased insulin sensitivity was reported in some studies (5, 6) while others could not find any association (7, 8). TSH is often elevated in obesity associated with disorders of lipid and glucose metabolism.
To elucidate the link between TSH and obesity, the relationship between TSH and adipocytokines were studied. Various adipocytokines such as leptin, adiponectin, interleukin 6, tumor necrosis factor α, visfatin and resistin have already been studied in hypothyroidism but controversial results were reported (9, 10, 11). The most promising adipocytokine is leptin. Leptin and TSH have similar circadian rhythms and leptin deficiency is associated with dysregulation in circadian rhythms of TSH. Leptin stimulates TSH production via hypothalamic–pituitary axis and TSH stimulates leptin production in adipocytes (12, 13). Weight loss was associated with a modulation of thyroid function that might be mediated by changes in leptin levels. The relationship of vaspin levels with hypothyroidism in humans was not studied to date. Two studies indicating a possible relationship between vaspin levels and thyroid dysfunction were conducted. One of them is an animal study that demonstrated that vaspin mRNA levels were significantly downregulated in hyperthyroid rats and increased in hypothyroid rats with respect to euthyroid rats (14). The other study showed a significant reduction in TSH levels after Roux-En-Y Gastric Bypass (RYGB), which was positively correlated with leptin and vaspin serum concentrations (15).
In this study, we aimed to investigate vaspin levels and its relationship with both anthropometric and insulin resistance parameters in subclinical and overt hypothyroid patients.
Methods
Subjects
In this study, 60 hypothyroid patients and 41 controls were enrolled. Twenty-seven of the patients were diagnosed as overt hypothyroid and 33 of them were diagnosed as subclinical hypothyroid. The study protocol was approved by the Ethics Committee of Hacettepe University School of Medicine and all participants gave their written informed consent before participating the study. Subjects with diabetes mellitus, renal or hepatic disease, acute or chronic inflammatory disease, cancer, acute or chronic infections, using any medication affecting thyroid function tests were excluded from the study. The control subjects were not suffering from any health problems and were not receiving any medications. We categorised the patients according to TSH ranges as follows: 0.36–4.5 (euthyroid group), 4.6–10 (subclinical hypothyroid group) and >10 μU/ml (overt hypothyroid group) (16). We perfomed two determinations of TSH to confirm the diagnosis of subclinical and overt hypothyroidism. We measured anti-thyroid peroxidase and anti-thyroglobulin levels in all subclinical and overt hypothyroid patients and thyroid ultrasonography was performed in all patients. The patients with autoimmune thyroid disease (confirmation with antibody positivity or sonographic appearance of thyroiditis) were included in the study. Overt hypothyroid patients were given Levothyroxine (LT4) sodium at a dose of 1.7 μg/kg per day. In patients with cardiovascular disease, LT4 sodium was started in small doses and slowly titrated. In a small group of patients (n=12), TSH levels were re-evaluated 2 months after the beginning of treatment and dose was titrated until the establishment of euthyroidism. These patients became euthyroid in an average of 3.8±1.4 months (range 2–6 months).
All subjects underwent a physical examination, detailed history and anthropometric measurements including BMI, waist-to-hip ratio (WHR) and blood pressure. BMI was calculated as weight divided by squared height (in kilograms per square metre). Waist circumference was measured from the narrowest point between the lowest rib and the uppermost lateral border of the iliac crest. The hip circumference was measured at their widest point. Blood pressure was measured twice in the same arm of each patient at rest for a minimum of 15 min and the mean value of the two measurements was used.
Laboratory analyses
Blood samples were drawn after an overnight fasting. They were centrifuged and immediately frozen in aliquots and stored at −80 °C until analysis. Triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) were measured using enzymatic calorimetric kits with intra- and inter-assay coefficients of variation (CV) of <10% (Roche Diagnostics GmbH). Fasting plasma glucose (FPG) concentration was determined by the glucose oxidase method (Olympus AU 2700, Beckman Coulter Inc.). Thyroid hormone levels, including TSH, free T4 (FT4) and free triiodothyronine (FT3), were measured by electrochemiluminescence immunoassay method (Roche Diagnostics GmbH). Serum fasting insulin was determined by chemiluminescence method (Roche Diagnostics GmbH). The average intra- and inter-assay CV for insulin were ≤4.3 and ≤3.4% respectively. Insulin resistance was quantified by the homoeostasis model assessment of insulin resistance index (HOMA-IR) calculated from the following formula: HOMA-IR=fasting insulin (in microunits per millilitre)×fasting glucose (in milligrams per deciliter)/405 (17). Serum vaspin levels were determined by a commercially available ELISA according to the manufacturer's instructions (Adipogen, Seoul, South Korea). The average intra- and inter-assay CV for vaspin were ≤3.6 and ≤9.06% respectively. Serum thyroid hormone levels (TSH, FT3 and FT4), lipid profile, fasting insulin, glucose and vaspin levels were measured after establishing euthyroidism in overt hypothyroid patients.
Statistical analysis
Statistical analysis was performed by the Statistical Package for the Social Sciences (SPSS v.11.0, Chicago IL, USA). Results were presented as mean±s.d. Normality of distribution was evaluated with Kolmogorov–Smirnov test. Statistical differences among the groups were analysed by one-way ANOVA followed by the Tukey's post hoc test for parametric variables. Non-parametric variables were analysed by Kruskal–Wallis and Mann–Whitney U test. Correlations among the study variables were tested by the Pearson or Spearman correlation coefficient. Analysis of covariance (ANCOVA) was used to adjust variables for BMI and age. A value of P<0.05 was considered as statistically significant.
Results
The baseline general characteristics of the study population are given in Table 1. In total 82 female (81.2%) and 19 male (18.8%) patients were included in the study. There was no significant difference in the distribution of gender between the groups (P>0.05). Overt hypothyroid patients had higher BMI than subclinical hypothyroid and euthyroid group (Table 1, P<0.05). Age, FPG, insulin and HOMA-IR were similar among the groups (Table 1). Patients with overt hypothyroidism had higher TG and lower HDL levels than euthyroid controls (Table 1, P<0.05), which disappeared after adjustment for BMI (P>0.05).
Clinical and laboratory characteristics of the study groups. Results are expressed as mean±s.d. (range).
| Overt hypothyroid | Subclinical hypothyroid | Euthyroid control | P | P1 | P2 | P3 | |
|---|---|---|---|---|---|---|---|
| n | 27 | 33 | 41 | – | – | – | |
| Age (years) | 40.74±11.80 (16–58) | 39.0±13.58 (17–62) | 35.37±10.52 (18–63) | NS | |||
| Sex (M/F) | 2 M/25 F | 7 M/26 F | 10 M/31 F | NS | |||
| BMI (kg/m2) | 30.04±6.35 (17.63–41.26) | 25.82±5.59 (16.65–35.63) | 25.91±5.30 (17.24–37.66) | <0.05 | <0.05 | <0.05 | NS |
| WHR | 0.84±0.11 (0.76–1.02) | 0.84±0.15 (0.67–1.53) | 0.82±0.09 (0.67–0.98) | NS | |||
| SBP (mmHg) | 122.52±21.00 (86–170) | 120.0±18.03 (85–159) | 118.31±14.51 (99–160) | NS | |||
| DBP (mmHg) | 80.16±10.90 (60–100) | 75.64±10.17 (50–92) | 77.17±11.64 (53–108) | NS | |||
| TSH (μIU/ml) | 37.65±31.77 (12.2–100) | 6.75±1.67 (4.6–9.89) | 2.33±.1.16 (0.39–4.59) | <0.001 | <0.001 | <0.001 | <0.001 |
| FT3 (pmol/l) | 4.39±1.42 (1.70–8.89) | 4.90±0.71 (3.74–6.78) | 4.86±0.57 (4.07–6.26) | NS | |||
| FT4 (pmol/l) | 9.07±3.01 (3.51–14.08) | 14.24±2.14 (10.24–18.2) | 15.61±1.80 (11.56–19.30) | <0.001 | <0.001 | <0.001 | <0.05 |
| FPG (mg/dl) | 91.15±13.43 (67–120) | 92.24±10.79 (67–119) | 86.74±12.24 (62–113) | NS | |||
| Insulin (μU/ml) | 12.43±5.93 (5.7–24) | 9.87±4.88 (2.1–22.0) | 10.27±4.09 (2.9–20.0) | NS | |||
| HOMA-IR | 2.89±1.69 (1.29–6.76) | 2.28±1.20 (0.35–5.81) | 2.21±0.96 (0.51–4.49) | NS | |||
| TC (mg/dl) | 201.67±51.12 (113–306) | 183.15±41.80 (119–273) | 181.00±40.95 (87–288) | NS | |||
| TG (mg/dl) | 140.77±74.83 (41–363) | 102.97±43.27 (46–248) | 98.78±75.38 (34–470) | <0.05 | NS | <0.05 | NS |
| HDL-C (mg/dl) | 48.96±12.30 (30.2–72.7) | 53.89±15.44 (33–99) | 58.15±14.72 (29–92) | <0.05 | NS | <0.05 | NS |
| LDL-C (mg/dl) | 126.44±45.27 (60–216) | 113.97±33.94 (64–185) | 108.12±34.37 (44–200) | NS | |||
| Vaspin (ng/ml) | 1.23±0.89 (0.23–4.22) | 1.42±1.13 (0.19–5.81) | 0.99±0.74 (0.21–3.38) | NS | |||
| Vaspin adj (ng/ml)a | 1.20±1.17 | 1.48±0.93 | 0.95±0.75 | NS | NS | NS | 0.063 |
P for three groups: P1, for overt hypothyroid and subclinical hypothyroid group; P2, for overt hypothyroid and euthyroid control group; P3, for subclinical hypothyroid and euthyroid control group; NS, Non-significant.
Mean±s.d. by general linear model with adjustment of age and BMI.
There was no difference in vaspin levels among the three groups (Table 1, P>0.05). After adjustment for BMI and age, a non-significant difference in vaspin levels between subclinical hypothyroid and euthyroid group was observed at a level of P=0.063. Also, there was no significant correlation between vaspin levels and BMI, WHR, FPG, fasting insulin and HOMA-IR values (P>0.05). Vaspin levels were not correlated with TSH, FT3 and FT4 levels (r=0.082, −0.070 and −0.083, respectively; P>0.05 for all). In each group, the analysis of vaspin in relation to BMI was calculated, but no significant correlation was observed (P>0.05).
Owing to gender difference in vaspin levels (3, 18) and small number of males included in our study, we further evaluated the relationship between vaspin levels and thyroid status in women. The baseline general characteristics of the women in our study group are given in Table 2. After adjustment for BMI, only FPG levels remained significant (P<0.05) between the groups. Similar to the analysis including whole patients, the analysis in women revealed no significant difference in vaspin levels among the groups. Even after adjustment for age and BMI, vaspin levels were similar between the groups (Table 2, P=0.077). We failed to find any correlation between vaspin levels and TSH, BMI, FPG, fasting insulin and HOMA-IR values in women (P>0.05).
Clinical and laboratory characteristics of the women in the study group. Results are expressed as mean±s.d.
| Overt hypothyroid | Subclinical hypothyroid | Euthyroid control | P | P1 | P2 | P3 | |
|---|---|---|---|---|---|---|---|
| n | 25 | 26 | 31 | – | – | – | |
| Age (years) | 40.68±12.18 | 39.27±12.91 | 34.35±10.81 | NS | |||
| BMI (kg/m2) | 30.12±6.62 | 26.29±5.76 | 25.22±5.25 | <0.05 | NS | <0.05 | NS |
| WHR | 0.88±0.06 | 0.84±0.17 | 0.79±0.07 | <0.05 | NS | <0.05 | NS |
| SBP (mmHg) | 120.96±21.04 | 119.42±19.15 | 116.32±14.98 | NS | |||
| DBP (mmHg) | 79.65±11.08 | 74.88±10.55 | 76.12±12.51 | NS | |||
| TSH (μIU/ml) | 39.07±32.62 | 6.82±1.69 | 2.48±1.21 | <0.001 | <0.001 | <0.001 | <0.001 |
| FT3 (pmol/l) | 4.32±1.45 | 4.86±0.75 | 4.76±0.52 | NS | |||
| FT4 (pmol/l) | 8.88±3.04 | 14.23±2.17 | 15.44±1.83 | <0.001 | <0.001 | <0.001 | NS |
| FPG (mg/dl) | 90.12±13.35 | 93.81±11.52 | 84.5±11.42 | <0.05 | NS | NS | <0.05 |
| Insulin (μU/ml) | 11.62±5.59 | 10.27±4.48 | 10.40±4.21 | NS | |||
| HOMA-IR | 2.66±1.59 | 2.41±1.17 | 2.17±0.95 | NS | |||
| TC (mg/dl) | 200.48±52.51 | 185.42±45.41 | 171.87±37.45 | NS | |||
| TG (mg/dl) | 141.28±76.33 | 102.77±47.83 | 85.77±45.79 | <0.05 | NS | <0.05 | NS |
| HDL-C (mg/dl) | 49.87±11.05 | 54.27±17.00 | 58.92±14.26 | NS | |||
| LDL-C (mg/dl) | 128.52±45.92 | 117.38±35.93 | 100.97±30.78 | <0.05 | NS | <0.05 | NS |
| Vaspin (ng/ml) | 1.17±0.87 | 1.64±1.17 | 1.11±0.79 | NS | |||
| Vaspin adj (ng/ml)a | 1.14±1.09 | 1.63±0.96 | 1.07±0.88 | NS |
P for three groups: P1, for overt hypothyroid and subclinical hypothyroid group; P2, for overt hypothyroid and euthyroid control group; P3, for subclinical hypothyroid and euthyroid control group; NS, Non-significant.
Mean±s.d. by general linear model with adjustment of age and BMI.
When we analysed the correlations between TSH levels and lipid profile, FPG, fasting insulin and HOMA-IR levels in the entire study cohort, we found a significant correlation between TSH and TC, TG and LDL-C levels (r=0.323, 0.231 and 0.327, respectively; P<0.05 for all). After controlling for BMI, TSH was still correlated with TC and LDL-C levels but not with TG (r=0.287, P<0.05; r=0.280, P<0.05; r=0.158, P>0.05 respectively). TSH, FT4 and FT3 were not correlated with FPG, insulin and HOMA-IR values (P>0.05).
We further analysed serum vaspin levels of 12 overt hypothyroid patients after normalisation of thyroid function. Treatment with LT4 sodium did not alter vaspin levels in overt hypothyroid patients (Table 3, P>0.05).
Change in the levels of vaspin after thyroid hormone replacement in overt hypothyroid patients. Results are expressed as mean±s.d.
| Before treatment (n=12) | After treatment (n=12) | P | |
|---|---|---|---|
| Vaspin (ng/ml) | 1.35±1.06 | 1.25±0.68 | NS |
| TSH (μIU/ml) | 32.33±23.68 | 1.86±1.64 | <0.05 |
| FT3 (pmol/l) | 4.11±1.29 | 5.16±1.29 | <0.05 |
| FT4 (pmol/l) | 8.89±2.56 | 19.16±4.55 | <0.001 |
NS, Non-significant.
Discussion
The relationship between hypothyroidism, obesity and insulin resistance is of clinical interest (19, 20, 21, 22). To elucidate the link between thyroid disorders and adipose tissue, various adipocytokines were previously studied (9, 10, 11), in which the most promising one was leptin. Controversial results are present about the relationship between thyroid disease and adipocytokines studied to date. Vaspin is a novel adipocytokine, i.e. supposed to have insulin-sensitising effects. Vaspin mRNA was found to be altered in hypothyroid and hyperthyroid rats (14). We herein present novel data that vaspin levels are neither altered in overt and subclinical hypothyroidism nor have a relationship with features of insulin resistance in hypothyroid patients.
Metabolic syndrome is known as a cluster of obesity, hyperglycaemia, dyslipidaemia and hypertension. The association between serum TSH and the components of metabolic syndrome varied in different studies. In some recent studies, thyroid dysfunction (23) and even TSH within the normal range (19, 24, 25) were reported to be associated with insulin resistance and components of metabolic syndrome. By contrast, some other studies failed to detect a significant association between TSH and insulin resistance (19, 21, 22, 26). It is difficult to prove a casual relationship between insulin resistance and thyroid hormones as both are influenced by weight status. Bastemir et al. (27) found that the relationship between thyroid hormones and features of insulin resistance disappeared after adjustment for BMI. Similar to the studies that failed to find an association between thyroid dysfunction and insulin resistance, hypothyroidism did not influence fasting insulin levels and HOMA-IR values in our study. Only overt hypothyroid patients had non-significantly higher values than other groups.
Vaspin is a novel adipocytokine with potential insulin-sensitising effects. In humans, expression of vaspin (SERPINA12) mRNA was detected in human VAT and subcutaneous adipose tissue (2). Vaspin expression was shown to increase from overweight to obesity and detected in patients with type 2 diabetes mellitus rather than individuals with normal glucose tolerance (2). In obese children, serum vaspin was positively correlated with TG, fasting insulin and HOMA-IR (28). In overweight women with polycystic ovarian syndrome, serum vaspin levels and its expression in omental adipose tissue were significantly elevated and decreased by metformin treatment in accordance with the decrease in insulin resistance (29). They also detected a significant positive association with vaspin and BMI and WHR. In a study including 150 subjects, a positive correlation between serum vaspin concentrations and the VAT area was shown (30). El-Mesallamy et al. (4) reported higher levels of vaspin in both non-obese and obese type 2 diabetes patients than control subjects. In contrast, serum vaspin levels were reported to be associated with BMI and insulin sensitiviy in subjects with normal glucose tolerance but not in patients with type 2 diabetes mellitus (3). We previously showed comparable vaspin levels in type 2 diabetic patients and controls but lower vaspin levels in the ones with microvascular complications (31). In a cross-sectional study, euglycaemic hyperinsulinaemic clamp (EHC) was performed in 83 non-diabetic subjects, neither glucose tolerance status nor insulin sensitivity both as measured using EHC and HOMA-IR, was found to be associated with serum vaspin levels (32). All these data indicate a controversy in the association of vaspin levels with insulin resistance. In our study, there was no association between vaspin levels and FPG, insulin, BMI or HOMA-IR values in hypothyroid patients. Glucose was reported to induce vaspin production and secretion from omental adipose tissue in a dose-dependent manner indicating that vaspin expression is induced by hyperglycaemia (29). Vaspin mRNA expression was found to be absent in lean normal glucose-tolerant individuals and was detected in type 2 diabetic patients (2). Only non-diabetic subjects were included in our study and this might be the cause of this lack of association. Moreover, the controversy in the association of vaspin with insulin levels may be due to different polymorphisms of serpins in different populations. Serpin genes represent a superfamily of proteins and ∼500 serpins have been identified in a variety of species including animals, viruses and plants (33). Human α-1 antitrypsin is located within a cluster of serpin genes and has a wide spectrum of protein variants and shows different polymorphic frequencies in different human populations (34). Polymorphism of different proteins of serpin family was reported in many previous studies (35, 36). Therefore, we may speculate that the controversy in the association between vaspin levels and insulin resistance may be due to certain polymorphisms of serpins in our population. Our previous study also demonstrated similar vaspin levels in diabetic and non-diabetic subjects. Further investigation is needed to clarify this issue.
There is only one study about the regulation of vaspin by thyroid hormones on rats (14). Gonzalez et al. investigated the regulation of vaspin gene expression in rat white adipose tissue in various physiological and pathophysiological settings that are associated with energy homoeostasis and insulin sensitivity. As disturbances in thyroid function alter insulin sensitivity and metabolic components, the authors investigated vaspin mRNA, glucose and insulin levels in hyperthyroid, euthyroid and hypothyroid rats. Vaspin mRNA levels were significantly downregulated in hyperthyroid rats and significantly increased in hypothyroid rats compared with euthyroid ones although no difference in insulin and glucose levels was observed (14). They concluded that vaspin expression was affected by thyroid status in rats. In our study, vaspin levels were not correlated with TSH levels. Vaspin might be differently regulated in humans and rodents. Although it was not meant to investigate the relation of vaspin levels with thyroid functions, one study examined the relationship between TSH and vaspin and leptin levels before and after weight loss by bariatric surgery (15). The regulation of TSH by leptin and the effect of weight loss on thyrotropin levels in association with leptin levels were previously shown in humans (37). Handisurya et al. (15) showed that RYGB induced a significant reduction in circulating TSH levels, which positively correlated with changes in leptin and vaspin levels. The authors concluded that it is not known if the changes in vaspin levels are related to TSH alterations after weight loss or due to other confounding factors. Vaspin levels after bariatric surgery may be affected by differential changes in the secretion of gastrointestinal peptides. In our study, vaspin levels were not correlated with TSH levels and did not differ between hypothyroid and euthyroid subjects. Treatment of overt hypothyroid patients did not alter vaspin levels. Our study demonstrated that vaspin secretion was not regulated by TSH. The changes in vaspin levels after bariatric surgery may be primarily related to altered secretion of gastrointestinal peptides rather than TSH levels per se (15).
The main limitation of our study is the small sample size. Large-scale studies are therefore needed to identify the role of thyroid hormones on the regulation of vaspin.
In conclusion, vaspin levels did not seem to be associated with subclinical and clinical hypothyroid states. In our study cohort, hypothyroid patients have comparable insulin resistance parameters to control subjects that may explain the results of our study indicating similar vaspin levels in hypothyroid and euthyroid states. Moreover, establishment of euthyroidism by LT4 treatment did not significantly change vaspin levels suggesting that euthyroid and hypothyroid states in the same patients have no influence on vaspin levels.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Acknowledgements
We acknowledge the assistance of Metin Odevci during the performance of vaspin assays and Jale Karakaya for statistics.
References
- 1↑
Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A, Hashimoto I, Okada T, Yasuhara A, Nakatsuka A, Shikata K, Hourai S, Futami J, Watanabe E, Matsuki Y, Hiramatsu R, Akagi S, Makino H, Kanwar YS. Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. PNAS 2005 102 10610–10615. doi:10.1073/pnas.0504703102.
- 2↑
Kloting N, Berndt J, Kralisch S, Kovacs P, Fasshauer M, Schön MR, Stumvoll M, Blüher M. Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes. Biochemical and Biophysical Research Communications 2006 339 430–436. doi:10.1016/j.bbrc.2005.11.039.
- 3↑
Youn BS, Klöting N, Kratzsch J, Lee N, Park JW, Song ES, Ruschke K, Oberbach A, Fasshauer M, Stumvoll M, Blüher M. Serum vaspin concentrations in human obesity and type 2 diabetes. Diabetes 2008 57 372–377. doi:10.2337/db07-1045.
- 4↑
El-Mesallamy HO, Kassem DH, El-Demerdash E, Amin AI. Vaspin and visfatin/Nampt are interesting interrelated adipokines playing a role in the pathogenesis of type 2 diabetes mellitus. Metabolism 2011 60 63–70. doi:10.1016/j.metabol.2010.04.008.
- 5↑
Rochon C, Tauveron I, Dejax C, Benoıt P, Capıtan P, Fabrıcıo A, Berry C, Champredon C, Thıeblot P, Grızard J. Response of glucose disposal to hyperinsulinaemia in human hypothyroidism and hyperthyroidism. Clinical Science 2003 104 7–15. doi:10.1042/CS20020154.
- 6↑
Stanicka S, Vondra K, Pelikánová T, Vlcek P, Hill M, Zamrazil V. Insulin sensitivity and counter-regulatory hormones in hypothyroidism and during thyroid hormone replacement therapy. Clinical Chemistry and Laboratory Medicine 2005 43 715–720. doi:10.1515/CCLM.2005.121.
- 7↑
Harris PE, Walker M, Clark F, Home PD, Alberti KG. Forearm muscle metabolism in primary hypothyroidism. European Journal of Clinical Investigation 1993 23 585–588. doi:10.1111/j.1365-2362.1993.tb00970.x.
- 8↑
Owecki M, Nikisch E, Sowinski J. Hypothyroidism has no impact on insulin sensitivity assessed with HOMA-IR in totally thyroidectomized patients. Acta Clinica Belgica 2006 61 69–73.
- 9↑
Pontikides N, Krassas GE. Basic endocrine products of adipose tissue in states of thyroid dysfunction. Thyroid 2007 17 421–431. doi:10.1089/thy.2007.0016.
- 10↑
Iglesias P, Alvarez Fidalgo P, Codoceo R, Díez JJ. Serum concentrations of adipocytokines in patients with hyperthyroidism and hypothyroidism before and after control of thyroid function. Clinical Endocrinology 2003 59 621–629. doi:10.1046/j.1365-2265.2003.01897.x.
- 11↑
Perez A, Cubero JM, Sucunza N, Ortega E, Arcelús R, Rodriguez-Espinosa J, Ordoñez-Llanos J, Blanco-Vaca F. Emerging cardiovascular risk factors in subclinical hypothyroidism: lack of change after restoration of euthyroidism. Metabolism 2004 53 1512–1515. doi:10.1016/j.metabol.2004.05.016.
- 12↑
Ortiga-carvalho TM, Oliveira KJ, Soares BA, Pazos-Moura CC. The role of leptin in the regulation of TSH secretion in the fed state: in vivo and in vitro studies. Journal of Endocrinology 2002 174 121–125. doi:10.1677/joe.0.1740121.
- 13↑
Menendez C, Baldelli R, Camiña JP, Escudero B, Peino R, Dieguez C, Casanueva F. TSH stimulates leptin secretion by a direct effect on adipocytes. Journal of Endocrinology 2003 176 7–12. doi:10.1677/joe.0.1760007.
- 14↑
Gonzalez CR, Caminos JE, Vázquez MJ, Garcés MF, Cepeda LA, Angel A, González AC, García-Rendueles ME, Sangiao-Alvarellos S, López M, Bravo SB, Nogueiras R, Diéguez C. Regulation of visceral adipose tissue-derived serine protease inhibitor by nutritional status, metformin, gender and pituitary factors in rat white adipose tissue. Journal of Physiology 2009 587 3741–3750. doi:10.1113/jphysiol.2009.172510.
- 15↑
Handisurya A, Riedl M, Vila G, Maier C, Clodi M, Prikoszovich T, Ludvik B, Prager G, Luger A, Kautzky-Willer A. Serum vaspin concentrations in relation to insulin sensitivity following RYGB-induced weight loss. Obesity Surgery 2010 20 198–203. doi:10.1007/s11695-009-9882-y.
- 16↑
Targher G, Montagnana M, Salvagno G, Moghetti P, Zoppini G, Muggeo M, Lippi G. Association between serum TSH, free T4 and serum liver enzyme activities in a large cohort of unselected outpatients. Clinical Endocrinology 2008 68 481–484. doi:10.1111/j.1365-2265.2007.03068.x.
- 17↑
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985 28 412–419. doi:10.1007/BF00280883.
- 18↑
Seeger J, Ziegelmeier M, Bachmann A, Lössner U, Kratzsch J, Blüher M, Stumvoll M, Fasshauer M. Serum levels of the adipokine vaspin in relation to metabolic and renal parameters. Journal of Clinical Endocrinology and Metabolism 2008 93 247–251. doi:10.1210/jc.2007-1853.
- 19↑
Roos A, Bakker SJ, Links TP, Gans RO, Wolffenbuttel BH. Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects. Journal of Clinical Endocrinology and Metabolism 2007 92 491–496. doi:10.1210/jc.2006-1718.
- 20↑
Fernandez-Real JM, López-Bermejo A, Castro A, Casamitjana R, Ricart W. Thyroid function is intrinsically linked to insulin sensitivity and endothelium-dependent vasodilation in healthy euthyroid subjects. Journal of Clinical Endocrinology and Metabolism 2006 91 3337–3343. doi:10.1210/jc.2006-0841.
- 21↑
Bakker SJ, ter Maaten JC, Popp-Snijders C, Slaets JP, Heine RJ, Gans RO. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. Journal of Clinical Endocrinology and Metabolism 2001 86 1206–1211. doi:10.1210/jc.86.3.1206.
- 22↑
Ortega E, Koska J, Pannacciulli N, Bunt JC, Krakoff J. Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals. European Journal of Endocrinology 2008 158 217–221. doi:10.1530/EJE-07-0592.
- 23↑
Luboshitzky R, Aviv A, Herer P, Lavie L. Risk factors for cardiovascular disease in women with subclinical hypothyroidism. Thyroid 2002 12 421–425. doi:10.1089/105072502760043512.
- 24↑
Knudsen N, Laurberg P, Rasmussen LB, Bülow I, Perrild H, Ovesen L, Jørgensen T. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. Journal of Clinical Endocrinology and Metabolism 2005 90 4019–4024. doi:10.1210/jc.2004-2225.
- 25↑
Garduno-Garcia Jde J, Alvirde-Garcia U, López-Carrasco G, Padilla Mendoza ME, Mehta R, Arellano-Campos O, Choza R, Sauque L, Garay-Sevilla ME, Malacara JM, Gomez-Perez FJ, Aguilar-Salinas CA. TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects. European Journal of Endocrinology 2010 163 273–278. doi:10.1530/EJE-10-0312.
- 26↑
Ruhla S, Weickert MO, Arafat AM, Osterhoff M, Isken F, Spranger J, Schöfl C, Pfeiffer AF, Möhlig M. A high normal TSH is associated with the metabolic syndrome. Clinical Endocrinology 2010 72 696–701. doi:10.1111/j.1365-2265.2009.03698.x.
- 27↑
Bastemir M, Akin F, Alkis E, Kaptanoglu B. Obesity is associated with increased serum TSH level, independent of thyroid function. Swiss Medical Weekly 2007 137 431–434.
- 28↑
Suleymanoglu S, Tascilar E, Pirgon O, Tapan S, Meral C, Abaci A. Vaspin and its correlation with insulin sensitivity indices in obese children. Diabetes Research and Clinical Practice 2009 84 325–328. doi:10.1016/j.diabres.2009.03.008.
- 29↑
Tan BK, Heutling D, Chen J, Farhatullah S, Adya R, Keay SD, Kennedy CR, Lehnert H, Randeva HS. Metformin decreases the adipokine vaspin in overweight women with polycystic ovary syndrome concomitant with improvement in insulin sensitivity and a decrease in insulin resistance. Diabetes 2008 57 1501–1507. doi:10.2337/db08-0127.
- 30↑
Chang HM, Park HS, Park CY, Song YS, Jang YJ. Association between serum vaspin concentrations and visceral adipose tissue in Korean subjects. Metabolism 2010 59 1276–1281. doi:10.1016/j.metabol.2009.11.021.
- 31↑
Gulcelik NE, Karakaya J, Gedik A, Usman A, Gurlek A. Serum vaspin levels in type 2 diabetic women in relation to microvascular complications. European Journal of Endocrinology 2009 160 65–70. doi:10.1530/EJE-08-0723.
- 32↑
von Loeffelholz C, Möhlig M, Arafat AM, Isken F, Spranger J, Mai K, Randeva HS, Pfeiffer AF, Weickert MO. Circulating vaspin is unrelated to insulin sensitivity in a cohort of nondiabetic humans. European Journal of Endocrinology 2010 162 507–513. doi:10.1530/EJE-09-0737.
- 33↑
Patson PA. Serpins and other serin protease inhibitors. Immunology Today 2000 21 354 doi:10.1016/S0167-5699(00)01638-8.
- 34↑
Brantly M, Nukiwa T, Crystal RG. Molecular basis of alpha-1-antitrypsin deficiency. American Journal of Medicine 1988 84 13–31.
- 35↑
Lind B, Thorsen S. A novel missense mutation in the human plasmin inhibitor (alpha 2-antiplasmin) gene associated with a bleeding tendency. British Journal of Haematology 1999 107 317–322. doi:10.1046/j.1365-2141.1999.01708.x.
- 36↑
Kabesch M, Carr D, Weiland SK, von Mutius E. Association between polymorphisms in serine protease inhibitor, kazal type 5 and asthma phenotypes in a large German population sample. Clinical and Experimental Allergy 2004 34 340–345. doi:10.1111/j.1365-2222.2004.01860.x.
- 37↑
Kozlowska L, Rosolowska-Huszcz D. Leptin, thyrotropin, and thyroid hormones in obese/overweight women before and after two levels of energy deficit. Endocrine 2004 24 147–153. doi:10.1385/ENDO:24:2:147.
