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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0841
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 9 3337-3343
Copyright © 2006 by The Endocrine Society

Thyroid Function Is Intrinsically Linked to Insulin Sensitivity and Endothelium-Dependent Vasodilation in Healthy Euthyroid Subjects

Jose-Manuel Fernández-Real, Abel López-Bermejo, Antoni Castro, Roser Casamitjana and Wifredo Ricart

Unit of Diabetes, Endocrinology, and Nutrition, Hospital of Girona Dr. Josep Trueta, 17007 Girona, Spain

Address all correspondence and requests for reprints to: J. M. Fernandez-Real, M.D., Ph.D., Unit of Diabetes, Endocrinology, and Nutrition, Hospital de Girona Dr. Josep Trueta, Ctra. França s/n, 17007 Girona, Spain. E-mail: uden.jmfernandezreal{at}htrueta.scs.es.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Levels of TSH respond to fluctuations in serum free T4 (fT4) but remain in a very narrow individual range. There exists current controversy regarding the upper limit of normal serum TSH values above which treatment should be indicated.

Objective: We aimed to study whether the individually determined fT4-TSH relationship was associated with plasma lipids, insulin sensitivity, and endothelial dysfunction in healthy subjects with strictly normal thyroid function according to recent recommendations (0.3–3.0 mU/liter).

Design: This was a cross-sectional study.

Setting: The study consisted of a cohort of healthy men from the general population (n = 221).

Main Outcome Measures: Oral glucose tolerance, insulin sensitivity (SI, minimal model), endothelium-dependent vasodilation (high-resolution ultrasound), and plasma lipids were measured in relation to thyroid function tests.

Results: Both serum TSH and fT4·TSH product were positively associated with fasting and postload insulin concentration and negatively with SI. After body mass index stratification, these associations were especially significant among lean subjects. Serum TSH and fT4·TSH product also correlated positively with fasting triglycerides and negatively with high-density lipoprotein cholesterol. In a multiple linear regression analysis, age (P = 0.007) and SI (P = 0.02) but not body mass index, fasting triglycerides, or serum high-density lipoprotein concentration contributed independently to 3.7 and 3.3%, respectively, of the variance in fT4·TSH. Those subjects over the median of fT4·TSH showed reduced endothelium-dependent vasodilation.

Conclusions: Thyroid function tests are intrinsically linked to variables of insulin resistance and endothelial function. It is possible that underlying factors lead simultaneously to increased serum TSH, insulin resistance, ensuing dyslipidemia, and altered endothelial function even within current normal TSH levels.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THERE IS A CONTINUUM between the euthyroid state and hypothyroidism as there is between normal and elevated serum TSH concentrations. Therefore, the distinction between a normal and elevated serum TSH level is somewhat arbitrary. It has been used to distinguish individuals with normal thyroid function, who may or may not have underlying thyroid pathology, from those with subclinical hypothyroidism. In current assays, the upper limit of the TSH reference range is approximately 4.5 mIU/liter (1).

In 2003 the American Association of Clinical Endocrinologists issued a statement encouraging "doctors to consider treatment for patients who test out of the boundaries of a narrower margin based on a target TSH level of 0.3–3.0 mIU/liter" (2). Respected authorities have even suggested that the range be further contracted to an upper limit of normal of 2.5 mIU/liter (3) and is the subject of deliberations by expert panels (4, 5, 6).

In euthyroid subjects it has been observed that serum thyroid hormone concentrations have an impact on cardiovascular health and plasma lipids. Low free T4 (fT4) concentration was found to be an independent risk factor for atherosclerosis in euthyroid subjects (7). However, the relationship between subclinical hypothyroidism and an atherogenic lipoprotein profile is still unclear (8, 9, 10, 11, 12, 13, 14, 15, 16, 17).

In addition to plasma lipids, thyroid hormone also influences directly the vascular system. In a small study, subjects with TSH values in the upper normal range (n = 6) had endothelial dysfunction characterized by impaired flow- mediated endothelium-dependent vasodilation in their conduit arteries (18). In another small study (19), patients with subclinical hypothyroidism (TSH range 4.11–15.04 mU/liter, n = 14) vasodilation to acetylcholine was reduced and increased after levothyroxine replacement. Importantly, serum T4 causes relaxation of skeletal muscle resistance arterioles (20), indicating the importance of thyroid hormones for vascular function. Thyroid hormones behave as vasodilators acting directly on vascular smooth muscle cells (21, 22). Hypothyroid subjects show increased systemic vascular resistance and vasoconstriction in systemic and renal vessels (21, 23).

At least two studies have suggested that thyroid function may cause dyslipidemia through altered insulin sensitivity in healthy subjects (24) and patients with type 2 diabetes mellitus (25).

Levels of TSH in an individual patient respond to fluctuations in serum fT4 but remain in a very narrow individual range and change very little unless the patient becomes hypothyroid or hyperthyroid (26). Studies of twins indicate that each of us has a genetically determined fT4-TSH set point or relationship (27). Within an individual, thyroid hormone concentrations are maintained within relatively narrow limits. Baloch et al. (28) estimated that a measured TSH difference of 0.75 mU/liter would be required to be significant in a given patient, a difference consistent with the narrow individual range observed by Andersen et al. (26).

We aimed to study whether this individually determined fT4-TSH relationship is associated with plasma lipids, insulin sensitivity, and endothelial dysfunction in subjects with strictly normal thyroid function according to recent recommendations (0.3–3.0 mU/liter) (2, 4). In theory, the association between insulin resistance and thyroid failure is difficult to demonstrate with raised TSH 5–10 mU/liter, and thus it should be more difficult when TSH falls within the reference range.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Two hundred twenty-one nondiabetic consecutive, unselected (except for glucose tolerance criteria) Caucasian men, participants in an ongoing epidemiological study of risk factor for cardiovascular disease in northern Spain, were included in the study. Subjects were randomly localized from a census, and they were invited to participate. The participation rate was 71%. A 75-g oral glucose tolerance test according to American Diabetes Association criteria was performed in all subjects. All subjects included in this study had fasting plasma glucose less than 7.0 mM and 2-h postload plasma glucose less than 11.1 mM after a 75-g oral test. Smokers were defined as any person consuming at least one cigarette a day in the previous 6 months. None of the subjects was taking any medication or had any evidence of metabolic disease other than obesity. All subjects reported that their body weight had been stable for at least 3 months before the study. Inclusion criteria were: 1) serum TSH values lower than 3 mU/liter; 2) body mass index (BMI, weight in kilograms divided by the square of height in meters) less than 40 kg/m2; 3) absence of any systemic disease; and 4) absence of any infections in the previous month.

Measurements

Each subject was studied in the research laboratory in fasting conditions. The room was quiet, lights were dimmed, and temperature was controlled at 23 C.

Insulin sensitivity

In those subjects who agreed (n = 135), insulin sensitivity was also measured using the frequently sampled iv glucose tolerance test with minimal model analysis. The procedure was initiated in each subject at 0830–0845 h. An iv catheter was placed in an antecubital vein of each arm. Baseline samples for glucose and insulin were drawn at 5, 10, and 20 min after iv placement. Baseline samples for fT4 and TSH determinations were also obtained. Then 0.3 g/kg glucose as 50% dextrose solution was then administered over 1 min. At 20 min after the completion of the glucose bolus, 0.03 U/kg insulin (Actrapid; Novo-Nordisk A/S, Bagsvaerd, Denmark) was delivered iv. This increase of insulin facilitates measurement of insulin sensitivity using the minimal model technique. Blood samples for glucose and insulin determinations were obtained from a contralateral antecubital vein up to 180 min.

Brachial artery vascular reactivity

All subjects were also invited to measure brachial artery vascular reactivity. Of the 135 who agreed to minimal model, 109 also agreed to participate in this exploration on a different day. Subjects who did not agree were similar in age, BMI, and smoking habits, compared with those who finally participated. High-resolution external ultrasound (128 x P/10 mainframe with a 7.5-MHz linear array transducer (SSH-140A; Toshiba, Tokyo, Japan) was used to measure changes in brachial artery diameter in response to reactive hyperemia (leading to flow-mediated endothelium-dependent dilation) and 400 µg sublingual glyceryl trinitrate (GTN), an endothelium-independent, direct smooth muscle dilator. The lumen diameter of the artery was defined as the distance between the leading edge of the echo of the near wall-lumen interface to the leading edge of the far wall-lumen interface echo. All scans were taken with an electrocardiogram triggered coincident with the end diastolic R wave. All images were recorded with a S-VHS videotape (MD-830AG; Panasonic, Osaka, Japan). Endothelial-dependent vasodilation was provoked secondary to hyperemia induced by inflation of a pneumatic tourniquet placed around the forearm, distal to the scanned part of the artery, up to a pressure of 300 mm Hg for 5 min, followed by sudden deflation. This maneuver is recognized to induce hyperemia and raise shear stress on the endothelial cells, which in turn release nitric oxide, producing compensatory vasodilation, which allows testing endothelial function. Endothelial-dependent vasodilation is expressed as the percentage of change in the arterial diameter 1 min after hyperemia. Reactive hyperemia is calculated as the percentage change between the maximum flow recorded in the first 15 sec after cuff deflation and the flow during the resting scan. Endothelial-independent vasodilation is induced after sublingual administration of a 400-µg metered dose of GTN, an exogenous nitric oxide donor (Solinitrina spray; Almirall Prodesfarma, Barcelona, Spain) and expressed as the percentage of change in the arterial diameter 3 min later.

A first scan was recorded after 10 min of resting in a quiet room in the supine position. At this moment, heart rate was recorded. Then the tourniquet was inflated for 5 min. A second scan was recorded during 90 sec, beginning 10 sec before cuff deflation. After at least 10 more minutes of rest, a new control scan was recorded. A last scan was recorded from 2 min after GTN administration during 70 sec. All images registered on super-VHS tape were analyzed afterward by two independent observers blinded to the stage of the experiment. Each observer analyzed the arterial diameter for three cardiac cycles for each condition, and these measurements were averaged.

Validation of this technique was performed through the evaluation of reproducibility inter- and intraobserver in 22 healthy subjects [12 men and 10 women, mean age 30.1 yr ± 2.1 (SD), BMI 22.6 kg/m2 ± 0.8]. Two observers performed measurements (A and B). Intraclass coefficient of correlation of fixed effects between observers A and B was 0.90. Coefficient of variation between means obtained by observers A and B was 9%. The coefficient of variation obtained by observer A was 3% and the repeatability [95% confidence interval (CI)] was 0.27 mm. In observer B the coefficient of variation was 4%, with a repeatability (95% CI) 0.39 mm. Within-subject variability in 5 consecutive days (five subjects) showed a coefficient of variation of 6 (observer A) and 2% (observer B). The GTN-induced vasodilation correlated with basal artery diameter (r = –0.67; P = 0.025) and flux-mediated vasodilation (r = 0.68; P = 0.021).

Analytical methods

Serum glucose concentrations were measured in duplicate by the glucose oxidase method with the use of a Glucose Analyzer II (Beckman Instruments, Brea, CA). The coefficient of variation was 1.9%. Total serum cholesterol was measured through the reaction of cholesterol esterase/cholesterol oxidase/peroxidase. High-density lipoprotein (HDL)-cholesterol was quantified after precipitation with polyethylene glycol at room temperature. Total serum triglycerides were measured through the reaction of glycerol-phosphate-oxidase and peroxidase. Serum insulin levels during the frequently sampled iv glucose tolerance test were measured in duplicate by monoclonal immunoradiometric assay (Medgenix Diagnostics, Fleunes, Belgium). Intra- and interassay coefficients of variation were lower than 6%. fT4 and TSH were measured by electrochemiluminescence (Roche Diagnostics, Basel, Switzerland) with intra- and interassay coefficients of variation less than 5%.

Statistical methods

Descriptive results of continuous variables are expressed as mean ± SD. A product of fT4·TSH was constructed as a measure of the T4-TSH set point relationship. TSH contributed to 85% of fT4·TSH variance. This index was previously used by Yagi et al. (29) and named thyrotroph T4 resistance index. This index quantitates the sensitivity of the thyrotrophs to the feedback regulation by thyroid hormone. T4 resistance index discriminated quite well the degree of the resistance to thyroid hormones in normal individuals and subjects with genetically acquired resistance to thyroid hormones, establishing the severity of this resistance.

Before statistical analysis, normal distribution and homogeneity of the variances were evaluated using Levene’s test, and then variables were given a log transformation if necessary. These parameters (fT4·TSH product, insulin sensitivity, triglycerides, endothelium-dependent and independent vasodilation) were analyzed on a log scale and tested for significance on that scale. The anti-log-transformed values of the means are reported in the tables. The relation between variables was tested using Pearson’s test, partial correlation tests, and multivariate linear regression analysis in a stepwise manner. We used {chi}2 test for comparisons of proportions and unpaired t test for comparisons of quantitative variables. Levels of statistical significance were set at P < 0.05. The analyses were performed using the program SPSS (version 11.0; SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Thyroid function and metabolic variables

Anthropometrical and biochemical variables of the study subjects are shown in Table 1Go. Seventy-three subjects were lean (BMI < 25 kg/m2), 104 overweight (BMI between 25 and < 30 kg/m2), and 44 were obese (BMI > 30 kg/m2). No significant differences were observed in thyroid function tests among BMI groups. Serum TSH tended to be linearly associated with BMI (r = 0.12, P = 0.07). Serum fT4 correlated negatively with waist to hip ratio in all subjects (r = –0.16, P = 0.02) but not with BMI (r = –0.08, P = NS). The association with waist to hip ratio was significant in lean subjects (r = –0.25, P = 0.03) but not the remaining subjects (r = –0.03, P = 0.6). Thyroid function tests were not associated with age, systolic and diastolic blood pressure, or heart rate. Free T3 was not associated with any parameter.


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  		TABLE 1. Anthropometrical and biochemical variables of the study subjects

 
As expected, serum fT4 was negatively associated with serum TSH (r = –0.16, P = 0.02). Interestingly, both TSH and fT4·TSH product (but not fT4 or free T3) were positively associated with fasting insulin concentration and insulin concentrations at 90 and 120 min of the oral glucose tolerance test (r coefficients between 0.14 and 0.17, P values between 0.01 and 0.03) but not fasting or postload serum glucose. After BMI stratification, we observed that these associations were especially significant among lean subjects (r coefficients between 0.31 and 0.45, P values lower than 0.0001).

Both TSH and fT4·TSH product were negatively associated with insulin sensitivity (Fig. 1Go, upper panel). The links between serum TSH and insulin sensitivity (r = –0.48, P = 0.01) and between fT4·TSH product and insulin sensitivity (r = –0.51, P = 0.008) were especially remarkable in lean subjects (n = 25).


Figure 1
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  		FIG. 1. Linear associations between fT4·TSH product and insulin sensitivity (upper panel), fasting triglycerides (middle panel), and HDL cholesterol (lower panel) in healthy euthyroid subjects. Note the logarithm scale in y-axis.

 
Serum TSH and fT4·TSH product also correlated positively with fasting triglycerides and negatively with HDL cholesterol (Fig. 1Go, lower panels), and this association was uniformly present in lean and obese subjects. After controlling for insulin resistance, these associations were no longer significant. No significant associations were observed concerning total cholesterol or low-density lipoprotein (LDL) cholesterol.

In a multiple linear regression analysis, age (P = 0.007) and insulin sensitivity (P = 0.02) but not BMI, fasting triglycerides, or serum HDL concentration contributed independently to 3.7 and 3.3%, respectively, of the variance in the fT4·TSH product.

Thyroid function and endothelial function

Thyroid function variables were not significantly associated with endothelium-dependent or endothelium-independent vasodilation. However, when the subjects were divided according to the median of the fT4·TSH product (Table 2Go and Fig. 2Go), those subjects over the median showed reduced endothelium-dependent vasodilation. The latter subjects had a significantly higher mean TSH value and a tendency toward increased fT4 concentration. In this subgroup, only T4 contributed to 13.3% of endothelium-dependent vasodilation after controlling for age, BMI, smoking status, and TSH (these were the variables most associated with endothelial function on univariate analysis; Table 3Go). In subjects with fT4·TSH product below the median, no independent association was seen.


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  		TABLE 2. Endothelial and vascular reactivity according to fT4·TSH

 

Figure 2
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  		FIG. 2. The 95% CI for the mean of endothelium-dependent vasodilation in healthy subjects below and above the median of the fT4·TSH product.

 

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  		TABLE 3. Linear multiple regression of endothelium-dependent vasodilation as dependent variable in subjects with fT4·TSH product over the median (1.62)

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is the first study that evaluates glucose tolerance, insulin sensitivity, and endothelial function in association with thyroid function in a relatively large sample of subjects. All the subjects had strictly normal fT4 and TSH concentrations. The present findings add to the current controversy of treatment guidelines in subclinical hypothyroidism.

Thyroid function and insulin sensitivity

Thyroid hormones play an essential role in a variety of metabolic and developmental processes in the human body. Most effects are mediated via mechanisms that stimulate resting metabolic rate, increase ATP expenditure, and modulate adrenergic receptor number and thus responsiveness to catecholamines. Thyroid hormones also influence carbohydrate metabolism in skeletal muscle and adipose tissue via the positive transcriptional regulation of the muscle/fat- specific GLUT4, and stimulate lipolysis. All these steps interact with insulin action (30).

Very recently, associations of insulin resistance with TSH levels in obese subjects have been reported by another group (31). In our study, serum TSH and fT4·TSH product were associated linearly and positively with fasting and postload insulin concentrations and fT4·TSH negatively with a strong measure of insulin sensitivity, using the minimal model method. This association was most significant among lean subjects. Thus, current findings could not be attributed to increased TSH values in obese subjects, as recently suggested (32, 33, 34). In fact, insulin sensitivity contributed to 3.3% of the variation of fT4·TSH, independently of BMI. It could be argued that this variation is modest but is similar to the variation in energy expenditure attributed to variations in thyroid function in euthyroid young men (2%) (35). Our observational data do not prove any causal association, but there are plausible biological explanations and other studies pointing in the same direction. Previous reports in healthy subjects or patients with type 2 diabetes suggested an interaction of TSH with insulin sensitivity in their association with plasma lipids (24, 25). In addition, a third common factor might interact simultaneously with the thyroid axis and insulin sensitivity. For instance, a mutation in the {alpha}-isoform of the thyroid hormone receptor has been recently described to lead to thyroid hormone resistance, low heart rate, and insulin resistance in an animal model (36).

Serum fT4 was negatively associated with serum TSH, and we observed a decrease in serum fT4 with the increase in waist to hip ratio. These patterns support alterations in thyroid function with normal pituitary feedback regulation (low fT4 associated with high TSH). However, the negative associations between fT4·TSH product with insulin sensitivity suggests peripheral resistance to thyroid hormone action with insulin resistance: the higher the fT4·TSH product, the higher the fT4 for a given TSH concentration, and the lower the insulin sensitivity. In old trials with thyroid hormones in obesity, a negative correlation between final weight loss and serum thyroid hormones was interpreted as indicating peripheral resistance to thyroid hormones in obesity (37). In fact, there are many reports of clinical tolerance to large doses of thyroid hormones in obese patients (38, 39, 40). We suggest that obesity-associated insulin resistance may be responsible for these observations.

We cannot also exclude a decreased peripheral deiodination of T4 with insulin resistance (41, 42). The deiodinases play an important role in the maintenance of circulating and tissue levels of thyroid hormones. T4 is converted to T3 via type 2 deiodinase in the brain, pituitary, and muscle. A decreased activity of type 2 deiodinase could result in decreased intracellular availability of active thyroid hormone in these tissues. The reduction in intracellular T3 would lead to increased serum TSH and decreased transcription of GLUT4 in insulin-sensitive tissues, such as skeletal muscle and adipose tissue, contributing to insulin resistance. Insulin resistance has been observed in obese women (41) and type 2 diabetic patients (42) carrying a polymorphism of the type 2 deiodinase gene. However, the associations reported here were observed in subjects with serum TSH lower than 3 mU/liter. No information concerning thyroid function was reported in those studies for comparison (41, 42).

In the context of thyroid function-insulin resistance relationship, the fT4·TSH product was also associated positively with fasting triglycerides and negatively with HDL cholesterol. Of note was that we found these associations, even in subjects with strict normal thyroid function tests. Because thyroid hormones stimulate HDL synthesis (43), the negative association could also be envisioned as thyroid hormone resistance. However, it is well known that insulin resistance per se may lead to these same abnormalities. In fact, after controlling for insulin resistance, these associations were no longer significant. It should be stressed that the fT4·TSH product probably does not represent thyroid function or status in its narrow sense.

The absence of significant relationship of thyroid function with total or LDL cholesterol may be due to the fact that we studied subjects with more strict criteria of normal thyroid function. TSH ranged up to 4.3 mU/liter in those studies in which a significant relationship has been described (24, 25).

Endothelial function

Previous works in very small series found decreased endothelium-dependent vasodilation in subjects with subclinical hypothyroidism or with high normal TSH values (18, 19). Our data show that the influence of thyroid function on endothelial function extends into the euthyroid range and possibly reflects the action of thyroid hormone. The effect of thyroid hormone on endothelial function may be seen in euthyroid individuals, with strictly normal thyroid function (18). Interestingly, the difference in TSH between those with fT4·TSH product above and below the median was in the range of the differences that would be required to be significant in a given patient (0.75 mU/liter) (28). In addition, we controlled for the confounding variables influencing endothelial function in these two subgroups of subjects (Table 2Go). Interestingly, fT4 positively influenced endothelium- dependent vasodilation only in subjects with fT4·TSH over the median, even after controlling for confounding factors. In these subjects, the variance in endothelial function was associated with fT4 and not with TSH, which is the earliest index of thyroid dysfunction. This finding may suggest that the association between insulin resistance and endothelial and thyroid function tests does not reflect alterations in thyroid status but alterations in more fundamental common cellular functions shared by the two systems.

This observation also hints at a possible threshold effect of thyroid function. We observed decreased endothelial function with increased TSH, and a tendency toward increased fT4, in subjects with fT4·TSH product over the median. Again, this finding suggests resistance to thyroid hormone action. In fact, serum fT4 correlated negatively with waist to hip ratio in lean subjects but was positively associated with endothelial function in the subgroup of subjects with fT4·TSH product over the median. We cannot exclude a different sensitivity to fT4 according to obese status.

On the other hand, the observations of the present study support the hypothesis of the existence of possible genetic variants influencing both endothelial function and serum TSH. Circulating TSH and/or T4 variations may not be physiologically significant but rather represent a phenotypic marker associated with these genetic variants. Alternatively, changes in circulating and/or tissue thyroid hormone concentrations may be one of the mechanisms underlying the association of thyroid pathway-related physiology with endothelial function. These hypotheses have also been recently suggested concerning the association of high normal TSH values and hypertension (44, 45).

In summary, thyroid function tests are intrinsically linked to variables of insulin resistance and endothelial function. It is possible that underlying factors lead simultaneously to increased serum TSH, insulin resistance, ensuing dyslipidemia, and altered endothelial function.


   Footnotes
 
This work was supported by research grants from the Ministerio de Educación y Ciencia (BFU2004-03654) and Instituto de Salud Carlos III (RCMN C03/08, RGDM G03/212, and RGTO G03/028).

Disclosure statement: The authors have nothing to declare.

First Published Online June 27, 2006

Abbreviations: BMI, Body mass index; CI, confidence interval; fT4, free T4; GTN, glyceryl trinitrate; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Received April 19, 2006.

Accepted June 16, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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