Association of Metabolic Syndrome Parameters with TT3 and FT3/FT4 Ratio in Obese Turkish Population

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1 METABOLIC SYNDROME AND RELATED DISORDERS Volume 10, Number 2, 2012 Ó Mary Ann Liebert, Inc. Pp DOI: /met Association of Metabolic Syndrome Parameters with TT3 and FT3/FT4 Ratio in Obese Turkish Population Ozlem Tarcin, M.D., 1 Gul Babacan Abanonu, M.D., 2 Dilek Yazici, M.D., 1 and Orhan Tarcin, M.D. 3 Abstract Background: Obesity and metabolic syndrome are major health problems worldwide, including Turkey. Recent studies have shown an association between thyroid function tests and metabolic syndrome parameters. In this study, we aimed to determine the frequency of metabolic syndrome in an obese Turkish population and the relationship between metabolic syndrome and thyroid functions. Materials and Method: We recruited 211 patients (187 females/24 males; mean age, years) with body mass index (BMI) > 30 kg/m 2 and no other hormonal pathology that could cause obesity. Anthropometric evaluation was followed by measurement of fasting blood glucose (FBG), insulin, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), total thyroxine (TT4), free T3 (FT3), and free T4 (FT4). Metabolic syndrome was defined according to the 2005 revision of the National Cholesterol Education Program Adult Panel III (NCEP ATP III) criteria. Insulin resistance was calculated from homeostasis model assessment of insulin resistance (HOMA-IR) formula. The TSH cutoff value was set at 2.5 mu/l. Results: Metabolic syndrome was diagnosed in 122 patients (58%). Metabolic syndrome positive patients had significantly higher FBG, triglycerides, FT4, systolic (SBP) and diastolic blood pressure (DBP), and statistically lower HDL-C and FT3/FT4 ratio than metabolic syndrome negative patients. TSH decreased with age and was not related with any metabolic syndrome parameters. The FT3/FT4 ratio negatively correlated with FBG, triglycerides, SBP, and DBP (P = 0.003, r =-38; P = 0.02, r =-0.28; P = 0.005, r =-0.35; and P = 0.007, r =-0.34, respectively); TT3 positively correlated with HOMA-IR (P = 0.006, r = 0.40), FBG (P = 0.009, r = 0.38), and waist circumference (P = 0.02, r = 0.34). Conclusion: Metabolic syndrome frequency was increased in our study population compared to the general population. Metabolic syndrome parameters (except HDL) correlated with TT3, FT4, and the FT3/FT4 ratio. FT4 levels were associated with obesity and metabolic syndrome independently of insulin resistance, whereas TT3 levels were associated with both insulin resistance and metabolic syndrome. This relationship can be explained by compensatory effects of TT3, and probably FT4, on energy expenditure and thermogenesis in obese people. Introduction Obesity is a health problem worldwide (including Turkey), frequently leading to insulin resistance and metabolic syndrome. The Turkish Diabetes Epidemiology Study (TURDEP-II), 1 a recent study that aimed to determine the diabetes prevalence and metabolic status in the Turkish population, has shown that 32% of Turkish population is obese and obesity has increased by 44% since 1998, especially in women. It has been reported that body mass index (BMI) was negatively associated with serum free thyroxine (FT4) and higher thyroid-stimulating hormone (TSH) levels; however, this finding was not confirmed by all studies. 2 4 The increasing prevalence of obesity has been associated with a parallel increase in metabolic syndrome prevalence, which on the other hand is related to increased cardiovascular risk and type 2 diabetes. 5 The Turkish Heart Association made a statement that metabolic syndrome prevalence in the Turkish population was 33.9% in 2005, 6 whereas it has been reported to be between 15% and 40% 1 Marmara University Medical School, Endocrinology and Metabolism, Istanbul, Turkey. 2 Haydarpasa Numune Training and Research Hospital, Internal Medicine, Istanbul, Turkey. 3 Acibadem University Hospital, Gastroenterology, Istanbul, Turkey. 137

2 138 TARCIN ET AL. around the world, varying according to the region, nationality, age, and gender The relationship between thyroid function and either insulin resistance or the metabolic syndrome is not clear. There are studies demonstrating that TSH positively correlated with insulin resistance and obesity. 14 In a Dutch cohort study performed in euthyroid subjects, an association of low normal FT4 levels and insulin resistance with four metabolic syndrome parameters (except hypertension) was found. 9 In the same study, it was observed that the homeostasis model assessment (HOMA) index showed significant negative correlation with FT4 and positive correlation with TSH. Wartofsky et al. reported that euthyroid subjects with TSH higher than 2.5 mu/l tended to be more obese and had higher triglyceride levels. 15 Thus, the upper limit of normal TSH range is still under debate, especially for obese people. 16 The aim of this study was to determine the frequency of metabolic syndrome in obese Turkish population and to investigate the relationship between metabolic syndrome and thyroid function. Materials and Methods Subjects A total of 246 obese patients with a BMI 30 kg/m 2 who applied to internal medicine and endocrinology outpatient clinics at Haydarpasa Numune Training Hospital were evaluated. The exclusion criteria for our study were: Past medical history of endocrine disease associated with obesity, overt thyroid dysfunction, chronic renal or hepatic failure, use of drugs that may influence insulin resistance and thyroid hormone levels, and use of antiobesity medications. Thirty-five of these patients were excluded because of drug usage, hypothyroidism, and polycystic ovary syndrome. In all, 211 (187 females and 24 males; mean age, years) were recruited to the study, which was approved by Haydarpasa Numune Training Hospital ethics committee. All subjects gave informed consent before participation. Study design Height, weight, waist circumference (WC), BMI, and systolic (SBP) and diastolic blood pressure (DBP) of patients were recorded. After a fasting period of at least 8 h, fasting blood glucose (FBG) and insulin, total cholesterol, triglycerides, highdensity lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), TSH, total triiodothyronine (TT3), total T4 (TT4), FT3, and FT4 were analyzed. Anti-thyroglobulin (Tg) and anti-thyroid peroxidase (TPO) antibodies were measured only in patients who were genetically susceptible to developing autoimmune thyroiditis. Insulin resistance was assessed using the HOMA-IR method described by Mathew et al. 17 Metabolic syndrome was defined according to the 2005 revision of the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. 18 Metabolic syndrome was diagnosed by the presence of three or more of the following criteria: (1) Triglycerides 150 mg/dl or treatment with triglyceride-lowering drugs, (2) HDL-C < 40 mg/dl for men and < 50 mg/dl for women or specific treatment for this lipid abnormality, (3) FBG 100 mg/dl or blood glucoselowering therapy, (4) SBP and/or DBP 130/85 mmhg or antihypertensive drug treatment in a patient with hypertension, and (5) WC > 102 cm for men and > 88 cm for women. The groups were named as metabolic syndrome positive [MS( + )] and metabolic syndrome negative [MS( - )]. The cutoff point for TSH was set at 2.5 IU/mL. Assays Serum glucose concentration, total cholesterol, HDL-C, LDL-C, and triglyceride levels were measured by enzymatic colorimetric assays (Roche Diagnostics GmbH). The intraassay and interassay coefficients of variation were 0.8% and 7.5% for glucose, 0.8% and 1.4% for total cholesterol, 0.8% and 1.7% for HDL-C, 1.1% and 1.8% for LDL-C, and 1.6% and 1.9% for triglycerides. Insulin concentrations were quantified with an Immulite analyzer using chemiluminescence immunometric method (DPC, Los Angeles, CA). The intraassay coefficients of variation and the total sensitivity were between 3.5% and 5.5% and 4.1% and 7.3%; normal ranges were miu/ml. Serum TSH, TT3, TT4, FT3, and FT4 levels were determined by electrochemiluminescence immunoassay (Roche Diagnostics GmbH, Mannheim, Germany). Intra- and interassay coefficients of variations were 4.5% and 5.1% for TT3, 4.9% and 7.2% for TT4, 1.8% and 3.6% for TSH, 2.7% and 3.7% for FT4, and 2.5% and 3.8% for FT3. Normal ranges were set at uiu/ml for TSH, ng/dl for TT3, mg/dl for TT4, pg/ml for FT3, and ng/dl for FT4. Serum anti-tg and anti- TPO antibody concentrations were measured by electrochemiluminescence immunoassay (Roche Diagnostics). The measuring range was IU/mL for anti-tg and IU/mL for anti-tpo. Insulin resistance was calculated using the following formula of HOMA-IR (mmol/l mu/ml) = fasting glucose (mmol/l) fasting insulin (miu/ml)/22.5. Statistical analysis Statistical analysis was performed using version 16.0 of SPSS (Statistical Package for Social Sciences) for Windows. Comparison between the groups was made by independent Student t-test for variables of normal distribution, Mann Whitney U-test for variables with a skewed distribution, and by chi-squared tests for categorical data. Correlations between thyroid function tests and metabolic syndrome components were assessed by either the Pearson or Spearman correlation tests, where appropriate: the Pearson correlation test was used for variables that were normally distributed, whereas the Spearman correlation test was used for skewed or ordinal variables. The level of statistical significance was set at P < 0.05 and all results were expressed as mean standard deviation (SD). Results A total of 187 of the 211 patients were women (89%). The mean age of study subjects was (minimum, 18; maximum, 73) years. Metabolic syndrome was diagnosed in 122 patients (58%). The biochemical and anthropometric characteristics of MS( + ) and MS( - ) groups are shown in Table 1. FBG, triglyceride levels, FT4, SBP, and DBP were significantly higher in the MS( + ) group than in the MS( - ) one, whereas HDL-C and the FT3/FT4 ratio were statistically lower in MS( + ) patients. HOMA-IR was slightly increased in the MS( + ) group, but the difference was not statistically significant.

3 METABOLIC SYNDROME IS RELATED TO TT3 AND FT4 IN OBESE PEOPLE 139 Table 1. Comparison of Demographic and Biochemical Parameters of Patients with and without Metabolic Syndrome MS( + )(n = 122) MS( - )(n = 89) P Table 2. Comparison of Demographic and Biochemical Parameters of the Patients According to Serum TSH Level TSH < 2.5 (n = 139) TSH 2.5 (n = 72) P Age NS Gender 113/9 74/15 NS (female/male) BMI (kg/m 2 ) NS Waist/height NS SBP <0.001 DBP <0.001 FBG <0.001 Insulin NS HOMA-IR NS Total cholesterol NS Triglycerides <0.001 HDL-C LDL-C NS FT FT NS FT3/FT TT NS TT NS TSH NS MS, metabolic syndrome; NS, not significant; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; HOMA-IR, homeostasis model assessment of insulin resistance; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; FT4, free thyroxine; FT3, free triiodothyronine; TT3, total T3; TT4, total T4; TSH, thyroid-stimulating hormone. The patients were evaluated according to TSH levels (TSH cutoff value = 2.5 mu/l). Seventy-two patients (34%) had TSH 2.5 mu/l, and they were younger than the remaining 66% of patients who had TSH levels < 2.5 mu/l (P = 0.01) (Table 2). In the high-tsh group, total cholesterol was significantly decreased, HDL-C was lower (though not statistically significant), and anti-tg was higher compared to the low-tsh group (P = 0.02, P = 0.05, and P = 0.03, respectively). We could not find any difference between the groups regarding FBG, insulin, triglycerides, LDL-C, HOMA-IR, SBP, and DBP. After adjustment for age, there was still no difference between the groups. TSH demonstrated a statistically significant positive correlation with anti-tg (P = 0.004; r = 0.48) and negative correlation with age (P = 0.03; r =-0.21). Forty-four patients of the MS( + ) group had TSH 2.5 mu/l and the remaining 78 patients had TSH below 2.5 mu/l. We could not find any relationship between TSH level and presence of metabolic syndrome (w 2 = 0.3; P = 0.58). TSH levels did not correlate with any of the metabolic syndrome components (Table 3). We assessed the associations between other thyroid function tests and metabolic syndrome components, and we observed that FT4 positively correlated with FBG (P = 0.007, r = 0.31), SBP (P = 0.01, r = 0.28), and DBP (P = 0.005, r = 0.32), whereas there was not any association between metabolic syndrome components and either FT3 or TT4 (Table 3). TT3 showed a significant positive association with FBG (P = 0.009, r = 0.38) and WC (P = 0.02, r = 0.34). In addition to these, TT3 correlated extremely with HOMA-IR (P = 0.006, r = 0.40) and exhibited significant association with BMI and waist-to-height ratio (P = 0.03, r = 0.31 and P = 0.02, r = 0.35, respectively). Age Gender 122/17 65/7 NS (female/male) BMI NS Waist/height NS SBP NS DBP NS FBG NS Insulin NS HOMA-IR NS Total cholesterol Triglycerides NS HDL-C LDL-C NS FT NS FT NS FT3/FT NS TT NS TT4 8,7 2, NS Anti-Tg TSH, thyroid-stimulating hormone; NS, not significant; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; HOMA-IR, homeostasis model assessment of insulin resistance; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; FT4, free thyroxine; FT3, free triiodothyronine; TT3, total T3; TT4, total T4; Tg, thyroglobulin. The FT3/FT4 ratio was calculated and found related to metabolic syndrome components. FBG, triglycerides, SBP, and DBP were very significantly negatively correlated with the FT3/FT4 ratio (P = 0.003, r =-38; P = 0.02, r =-0.28; P = 0.005, r =-0.35; and P = 0.007, r =-0.34, respectively). HOMA-IR was higher than 2.6 in 127 patients (60%). In this group, WC, waist-to-height ratio, SBP, and DBP were statistically higher (P = 0.01, P = 0.005, P = 0.02, and P = 0.04, respectively), whereas HDL-C was lower than in the patients with HOMA-IR < 2.6 (P = 0.04). HOMA-IR showed a statistically positive correlation with WC, waist-to-height ratio, BMI, SBP, and DBP (P < 0.05 for all; r = 0.32, r = 0.33, r = 0.26, Table 3. Correlation Coefficients (r) Between Thyroid Function Tests and Metabolic Syndrome Components FT4 FT3/FT4 TT3 Waist circumference * SBP 0.28** ** 0.17 DBP 0.32** ** 0.22 FBG 0.31** ** 0.38** HDL-C Triglycerides * HOMA-IR ** *P < **P < FT4, free thyroxine; FT3, free triiodothyronine; TT3, total T3; SBP, systolic blood pressure; DBP, diastolic blood pressure; FBG, fasting blood glucose; HDL-C, high-density lipoprotein cholesterol; HOMA- IR, homeostasis model assessment of insulin resistance.

4 140 TARCIN ET AL. r = 0.27, and r = 0.20, respectively) and negative correlation with HDL-C (P = 0.006; r =-0.27). Waist-to-height ratio was extremely correlated with body weight and BMI (P < 0.001, r = 0.79 and P < 0.001, r = 0.73, respectively). Discussion Obesity is a growing worldwide problem, and the prevalence of metabolic syndrome increases in parallel with obesity. The prevalence of metabolic syndrome has been reported to be between 15% and 40% around the world, and 33.9% in the Turkish population in ,7 In our study, 58% of obese subjects had metabolic syndrome, which is a rate extremely higher than in the general population. This finding supports the hypothesis that weight gain and obesity may increase the risk of metabolic syndrome. We detected metabolic syndrome predominantly in women, which is a common finding of other studies. The reason for that could be both genetic factors and eating habits of women in Turkey. Thyroid dysfunction, especially hypothyroidism, is associated with weight gain and changes in body composition that are similar to those in metabolic syndrome. The relationship between insulin resistance, which is the key feature of metabolic syndrome, and hypothyroidism is not certain. Studies performed in 1990s reported normal serum thyroid concentrations and metabolism in obese subjects, similar to control subjects. 19,20 Stephan et al. found that insulin resistance was associated with high-normal TSH levels and, on the other hand, with elevated LDL-C, thus leading to increased cardiovascular risk. 21 Recent evidence has shown that obesity is associated with increased serum TSH levels, and also high-normal TSH level is related to the metabolic syndrome. 22,23 Moreover, another study demonstrated that TSH receptor polymorphisms detected among different races can influence the plasma TSH and thyroid hormone concentration. 24 In our study, we could not find any correlation between TSH levels and either metabolic syndrome components or presence of metabolic syndrome (Fig. 1). Serum TSH levels were positively correlated only with anti-tg levels and decreased with age. This result may be explained by the fact that only obese subjects were included in this study and we could not compare the parameters with those of lean people. Number of patients TSH 2.5 mu/l TSH <2.5 mu/l FIG. 1. Metabolic syndrome frequency in patients with thyroid-stimulating hormone (TSH) below and above 2.5 mu/l. (Black) MS( - ), metabolic syndrome negative; (gray) MS( + ), metabolic syndrome positive. In the present study, metabolic syndrome components exhibited an unexpected relationship with FT4 levels and the FT3/FT4 ratio. The most interesting finding was the positive correlation between FT4 and metabolic syndrome. Roos et al. first revealed an association between low-normal serum FT4 levels and increased insulin resistance in 1581 euthyroid subjects. 9 The authors also found a negative correlation between the HOMA index and FT4. In the same study, it was observed that four of the five metabolic syndrome traits (except hypertension) were significantly associated with FT4 level when adjusted for age and sex. Alevizaki et al. have reported a negative correlation between FT4 levels and subcutaneous fat thickness in euthyroid healthy individuals. 4 The authors have suggested that FT4 is an independent predictor of subcutaneous fat in euthyroid subjects. However, in another study, a relationship between FT4 and presence of metabolic syndrome in healthy euthyroid individuals could not be found after age adjustment. 8 The authors concluded that because serum FT4 tends to decrease with age, the interaction between FT4 and metabolic syndrome components should be evaluated according to age and gender as well. Similar to the study performed by Kim et al., 8 we found that FT4 decreased with age and positively correlated with two metabolic syndrome components (i.e., FBG and blood pressure), BMI, waist-to-height ratio, and metabolic syndrome presence in our study population, but not with HOMA-IR. The effects of thyroid hormones on glucose homeostasis have already been shown in previous studies, 25 and they explain the positive correlation between FBG and FT4, even after adjustment for age. On the other hand, the correlation between SBP and DBP and FT4 can be explained by the hypothesis that a possible link exists between high pituitary thyroid axis set point or resistance to thyroid hormones, and factors associated with elevated blood pressure (e.g., endothelial dysfunction). 14,26 According to these findings, we assume that FT4 is related to metabolic syndrome in patients with obesity independently of insulin resistance, but the pathophysiology has not been clarified yet. The FT3/FT4 ratio was inversely correlated with metabolic syndrome components (except HDL-C), perhaps caused by the positive relation between FT4 and these components. However, this ratio showed more meaningful association with metabolic syndrome than FT4 alone. The FT3/FT4 ratio did not change with age and correlated to neither HOMA nor BMI. De Pergola et al. 20 suggested an increased conversion of FT4 to FT3 in 201 obese and overweight euthyroid women, although this hypothesis was not proved. All patients in our study were extremely obese, and peripheral conversion of FT4 to FT3 could be more evident in obesity alone than in metabolic syndrome. In most of the studies investigating the link between thyroid functions and obesity, only free thyroid hormones were evaluated, whereas we performed measurements of both total and free thyroid hormones. In our study, no correlation could be found between FT3 and either HOMA-IR or metabolic syndrome components, whereas TT3 levels, but not TT4, were associated with both HOMA-IR and metabolic syndrome. The only thyroid hormone that correlated with insulin resistance (HOMA-IR) in the present study was TT3. Because TT3 especially regulates both the resting metabolic rate and thermogenesis, changes in thyroid hormone (particularly TT3) concentrations can alter the adaptation process

5 METABOLIC SYNDROME IS RELATED TO TT3 AND FT4 IN OBESE PEOPLE 141 in obesity. 27 The obesity-associated elevation of FT3 levels may be a compensatory mechanism for the increased central fat accumulation. 28 The change in serum TT3 levels during weight gain was well described by Rosenbaum et al., and the authors suggested that whatever effect the changes in serum TT3 exert on changes in energy expenditure appear to be associated with sympathetic nervous system tone and these effects are reversible. 29 Moreover, T3 is described as the most powerful physiologic stimulator of thermogenesis which affects lipogenesis and increases food intake. 30 The reason for indifferent TT3 levels between MS( + ) and MS( - ) groups could be that the study included only severely obese people (with BMI 30 kg/m 2 ). However, the positive correlation of TT3 with HOMA-IR, WC, and BMI in our study can be explained by the compensatory effects of TT3 on energy expenditure and thermogenesis in obese people, which supports the thesis mentioned in the studies above Another interesting finding of our study was the significant correlation between HOMA-IR and waist-to-height ratio (P = and r = 0.34). Kondaki et al. examined 1097 European adolescents and reported that waist-to-height ratio and WC were more strongly associated with insulin resistance proxy measures compared to the rest of the anthropometric indices including skin fold sum, BMI, and fat mass. 32 Several studies have shown that waist-to-height ratio was more strongly associated with cardiovascular risk factors (e.g., hypertension, hyperglycemia, hypertriglyceridemia) and the metabolic syndrome than BMI or WC, especially in obese populations Recently, 6971 subjects from the Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment (DETECT) study were evaluated by comparing WC and waist-to-height ratio to find their predictive values for diabetes and cardiovascular risk. 37 The authors have hypothesized that short subjects with the same cutoff point as tall ones have higher cardiovascular risk factors, owing to more abdominal fat than in tall subjects. As a result of the study, although there was no difference in prevalence of metabolic syndrome according to both indices, short subjects had increased risk factors and 30% prevalence of the metabolic syndrome than tall subjects if grouped by WC but not if grouped by waist-to-height ratio. Thus, the authors have suggested that waist-to-height ratio, instead of WC, should be applied in the metabolic syndrome definition. In our study group, the associations between HOMA and either waist-to-height ratio or WC were similar to each other (P = 0.001, r = 0.33 and p = 0.002, r = 0.31, respectively). There was a positive correlation between waist-to-height ratio and blood pressure, whereas WC did not correlate with any of the metabolic syndrome components. These findings support previous studies regarding the association of waist-to-height ratio with the metabolic syndrome and insulin resistance; thus, waist-to-height ratio can be used instead of WC when defining metabolic syndrome, or both of them can be applied. The limitation of our study was the small sample size. If more subjects could have been recruited to the study, the significance of correlations and differences could be more prominent. There is still ambiguity about the link between thyroid function and either obesity or metabolic syndrome. Thus, well-designed, prospective, controlled studies are needed to clarify these relationships. In conclusion, metabolic syndrome frequency was increased in obese Turkish subjects compared to the general population. Three of metabolic syndrome parameters (except HDL-C and triglycerides) were related to TT3 and FT4. Moreover, FT4 levels were associated with obesity and metabolic syndrome independently of insulin resistance, whereas TT3 levels were associated with both insulin resistance and metabolic syndrome in our study. This relationship can be explained by the compensatory effect of TT3, and probably FT4, on energy expenditure and thermogenesis in obese people. Additionally, we suggest that waist-to-height ratio may be considered as a new marker of insulin resistance and may be useful in the definition of the metabolic syndrome. Author Disclosure Statement The authors have nothing to disclose. References 1. Satman I, Group TS. Turkish Diabetes, Hypertension, Obesity and Endocrinologic Diseases Prevalence Study (TURDEP)-II Unpublished study, available from 2. Reinehr T. Obesity and thyroid function. Mol Cell Endocrinol 2010;316: Knudsen N, Laurberg P, Rasmussen LB, et al. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. 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