THYROID

Volume 21, Number 9, 2011

Mary Ann Liebert, Inc.
DOI: 10.1089/thy.2010.0402

ORIGINAL STUDIES, REVIEWS,

AND SCHOLARLY DIALOG
THYROID FUNCTION AND DYSFUNCTION

The Association of Insulin Resistance

with Subclinical Thyrotoxicosis
Jorge Rezzonico,1 Hugo Niepomniszcze,2 Mariana Rezzonico,1 Eduardo Pusiol,2
Marcelo Alberto,1 and Gabriela Brenta 3

Background: Although overt thyrotoxicosis is associated with reduced insulin sensitivity (IS), the effects of
subclinical thyrotoxicosis (SCTox) (i.e., suppressed serum thyroid-stimulating hormone with free thyroxine and
tri-iodothyronine within the reference range) on glucose metabolism are not clear. SCTox may be of endogenous
origin or due to ingestion of supraphysiological amounts of thyroid hormone. Our hypotheses were that reduced
IS is present in SCTox and that the degree of reduction differs between SCTox of endogenous and exogenous
origin.
Methods: The study population consisted of 125 premenopausal, normal-weight women, divided into four
groups: exogenous SCTox due to L-T4 treatment for benign goiter or hypothyroidism (SCTox-ExogG) (n 53),
endogenous SCTox (SCTox-Endog) (n 12), exogenous SCTox due to L-T4 treatment for differentiated thyroid
cancer (SCTox-ExogDTC) (n 20), and finally euthyroid women (C) (n 40) as a control group. After a mixed
meal challenge, glucose and insulin were determined at baseline and 120 minutes later. IS was assessed by
homeostasis model assessment of insulin resistance (HOMA-IR) index, quantitative IS check index (QUICKI),
and 2 hours IS Avignons index amended by Aloulou for mixed food. Secretion by pancreatic B-cells was
calculated by HOMA-B index. Comparison among groups was done by analysis of variance followed by Tukey
test. Linear regression analysis of T3 versus HOMA-IR was calculated.
Results: IS was reduced in all types of SCTox when compared with C. All SCTox groups had significantly higher
levels of insulin (baseline and postmeal) and HOMA-IR and lower values of QUICKI and Aloulou when
compared with controls. SCTox-Endog, however, had higher baseline insulin levels and HOMA-IR and a lower
QUICKI index than the rest of the SCTox groups. Although within the normal range, total T4, free T4, and T3
levels were also significantly higher in the SCTox groups than in euthyroids. In SCTox-Endog, T3/T4 ratio was
increased above the rest of SCTox groups. A moderate linear relationship between T3 and HOMA-IR was found
in the whole population.
Conclusions: IR is associated with SCTox of either endogenous or exogenous origin. However, based on our
findings of lower IS compared with the rest of the SCTox groups, the endogenous subclinical form might have an
even larger metabolic impact.

Introduction

he relationship between thyroid dysfunction and

glucose homeostasis has long been studied, with overt
thyrotoxicosis being the epitome of how impaired thyroid
function can lead to IR. A clear example of this dysregulation
in clinical practice is the worsening of glucose control in diabetics who become hyperthyroid (1). The main alterations
advocated to explain this phenomenon include increased

endogenous glucose output by the liver, both through a direct

effect of T3 on gluconeogenesis (2) and also acting at the hypothalamus, increasing functionally reciprocal sympathetic
and parasympathetic autonomic outputs to the liver (3). Simultaneously, an impaired response to insulin stimulation of
major intracellular pathways of glucose metabolism in peripheral tissues prevails (4). Although the pathophysiology
behind peripheral IR has not been fully elucidated, a lower
glucose extraction from serum in proportion to increased

Presented as a poster (p-0707) at the 14th International Thyroid Congress, Paris, France, September 1116, 2010.
1
Endocrinology Unit, Centro Privado de Endocrinologa, Mendoza, Argentina.
2
Division of Endocrinology, Hospital de Clnicas-University of Buenos Aires, Buenos Aires, Argentina.
3
Division of Endocrinology, Cesar Milstein Hospital, Buenos Aires, Argentina.

945

946
blood flow levels in overt hyperthyroid patients has been
demonstrated (5). Moreover, it has been suggested that an
increased secretion of IL6 and TNFa can be implicated in the
IR found in peripheral tissues (6).
Subclinical thyrotoxicosis (SCTox) has been also associated
with IR (7,8) in some but not all studies (9). Part of this controversy, despite a common biochemical definition, might lie
in the heterogeneous nature of SCTox. Although suppressive
thyroid-stimulating hormone (TSH) treatment with levothyroxine (L-T4) aimed at benign goiter shrinkage is of
uncertain value, exogenous SCTox from this treatment is still
frequently encountered. On the other hand, some differentiated thyroid cancer (DTC) patients do not have any
alternative to L-T4 suppressive treatment. Further, the previously reported (10,11) positive relationship between DTC
and IR may add to this lack of consensus. Finally, endogenous
SCTox, resulting from longstanding autonomous nodular
goiter or Graves disease, also represents a potential source of
IR with an unrecognized clinical impact.
As data about a possible association between SCTox and IR
are controversial, we performed a study to look for differences
in insulin sensitivity (IS) among euthyroid subjects, patients
with SCTox of endogenous origin, and patients with goiter
and thyroid cancer who had SCTox of exogenous origin.

REZZONICO ET AL.
This study was approved by the ethics committee of our
institution. Written informed consent was obtained from all
subjects before initiating the study.
Clinical and biochemical measurements
A clinical history and physical examination that included
anthropometric measurements was performed in all participants. Patients were barefoot when weight and height were
assessed. BMI was calculated as weight over height squared
(kg/m2). All study patients had total T4, free T4, T3, TSH, and
antithyroperoxidase (ATPO) levels assayed within 7 days
before entry into the protocol. To make the diagnosis of goiter,
an ultrasonogram was performed and thyroid volume was
calculated. Thyroid volumes larger than 12 mL (20) and mixed
or solid nodules larger than 5 or 3 mm in diameter, respectively, met the criteria for goiter.
After measuring baseline glucose and insulin levels, a
standard mixed breakfast (812 calories, 66% from carbohydrate, 11% protein, and 22% fat) (15,21,22) was taken by the
subjects. After breakfast the subjects rested until blood glucose and insulin were measured again at 2 hours after this
meal. Insulin sensitivity and secretion were calculated using
the following equations:
HOMA-IR SG0 SI0 =405

Materials and Methods

Population
This study included 125 women who were nonobese (body
mass index [BMI] <30), 1855 years of age, and lived in an
area that was currently iodine sufficient (12). They had consulted at our Endocrinology Center at Mendoza in the period
from 2004 to July 2009. Exclusion criteria were pregnancy,
smoking, severe liver or kidney disease, major depression,
psychosis, treatment with metformin, lithium, beta blockers,
amiodarone, antithyroid drugs, tri-iodothyronine, TRIAC, or
iodine and women treated at doses below 50 mg per day of LT4 (13). Women with known diabetes or those with fasting
glucose serum levels greater than 125 mg/dL (14) or postprandial blood glucose greater than 150 mg/dL (15) were also
excluded.
The population was divided into four groups: exogenous
SCTox due to L-T4 treatment for benign goiter or L-T4 overdosage (SCTox-ExogG) (n 53), endogenous SCTox (SCToxEndog) (n 12), exogenous SCTox due to L-T4 treatment for
(SCTox-ExogDTC) (n 20), and euthyroid women (C) as a
control group (n 40). The C group was composed of individuals undergoing evaluation for irregular menses (n 6),
health checkup (n 10), pseudogoiter (n 2), friends advice
(n 5), excessive perspiration (n 4), weight control (n 9),
hirsutism (n 2), edema (n 2) who were found to not have
ongoing thyroid dysfunction, thyroid autoimmunity, or goiter. We defined SCTox as TSH levels <0.3 mU/L, free T4
<1.8 ng/dL, total T4 <12.0 mg/dL, and T3 <180 ng/dL.
After a mixed meal test, glucose and insulin were determined at baseline and 120 minutes later. IS was assessed by
homeostasis model assessment of IR (HOMA-IR) index (16),
quantitative IS check index (QUICKI) (17), and 2 hours IS
Avignons index amended by Aloulou for mixed meal (18,19).
Secretion by pancreatic B-cells was calculated by the index of
b-cell function derived from the homeostatic model (HOMAB) (16).

QUICKI 1=log SG0 log SI0

HOMA-B 20 SI0 =SG0 =18  3:5
Aloulou index:
2812 67 105=SG2h SI2h apparent volume of
distribution of SG 150 mL kg body weight
where SG serum glucose (mg/dL) and SI serum insulin
(mIU/mL), measured at baseline (0) and 2 hours (2h).
Both QUICK (17) and HOMA-IR (16) are considered surrogates of central IS (23) and we used them to assess IR in the
liver. Aloulou index, which takes into account the values of
postprandial glucose and insulin levels, was used to assess
peripheral glucose sensitivity (22, 23).
Normal values of postprandial blood glucose were considered to be 112 mg/dL or less. Glucose intolerance was defined
by glucose levels of 113150 mg/dL at 2 hours after the standard mixed breakfast (22). All blood samples were drawn after
12 hours of fasting without any medication. Except for the
determination of glucose that was performed immediately,
serum samples were frozen and stored until assay at 208C.
Total T4, free T4, and T3 were all measured with a competitive chemiluminescent enzyme immunoassay method in
solid phase (IMMULITE; Siemens, Los Angeles, CA). Reference values for total T4 were 4.512.5 mg/dL; they were
0.71.8 ng/dL for free T4 and 90180 ng/dL for total T3. TSH
was measured with a noncompetitive chemiluminescent
enzyme immunoassay method in solid phase (IMMULITE).
Reference values for serum TSH were 0.34.5 mU/L. ATPO
and antithyroglobulin (anti-TG) antibodies were assessed by a
sequential enzyme immunometric assay chemiluminescent
solid phase (IMMULITE). Reference values were less than
20 IU/mL for both TPO and TG antibodies. Insulin was
measured by enzyme immunometric assay with a two-site
chemiluminescent solid phase (IMMULITE). Reference values
for 2 hours postprandial insulin were less than 10.0 mIU/mL.

INSULIN RESISTANCE AND SUBCLINICAL THYROTOXICOSIS

947

Table 1. Thyroid Status (Mean  Standard Deviation)

Variable

ANOVA p-value

SCTox-ExogG

SCTox-Endog

SCTox-ExogDTC

T4
Free T4
T3
TSH
T3/T4

<0.0001
0.0004
<0.0001
<0.0001
<0.0001

10.48  1.44
1.42  0.27
135  19
0.16  0.10
12.21  1.47

10.31  1.73
1.53  0.19
150  16
0.15  0.13
14.45  0.76b

10.50  1.51
1.53  0.27
138  19
0.12  0.11
12.99  .48

7.28  1.31a
1.12  0.19a
113  13a
1.99  0.73a
13.97  3.23

p < 0.05 between the control group and the SCTox groups by Tukey post hoc analysis.
p < 0.05 between the SCTox-Endog group and the rest of the SCTox groups by Tukey post hoc analysis.
SCTox-ExogG, subclinical thyrotoxicosis due to levothyroxine (L-T4) treatment for benign goiter or L-T4 overdosage; SCTox-Endog,
endogenous subclinical thyrotoxicosis; SCTox-ExogDTC, exogenous subclinical thyrotoxicosis due to L-T4 treatment for differentiated
thyroid cancer; C, euthyroid women; ANOVA, analysis of variance.
b

Glucose was measured by an enzymatic method using

glucose oxidase/peroxidase (Roche Diagnostics, Mannheim,
Germany); reference values were 70110 mg/dL. The measurement of glucose was performed in collected plasma from
blood with EDTA/fluoride, so as to avoid errors by enzymatic
destruction of blood glucose (glycolysis).
Statistical analysis
Statistical analysis was performed with SPSS software
package (SPSS, Chicago, IL). Values are presented as
mean  SD. Comparison among groups was done by analysis
of variance (ANOVA) followed by Tukey test. Transformations were used to achieve homogeneity of variance: log in
the case of basal serum insulin and ranks for postprandial
serum glucose and insulin levels and HOMA-IR, QUICKI,
and Aloulou indexes. Weighted least squares were used for
TSH and T3/T4. Linear regression analysis of T3 versus
HOMA-IR was calculated. Differences were considered significant at p less than or equal to 0.05.
Results
The SCTox-ExogG group was comprised of 20 patients
with multinodular goiter, and of them, fine-needle aspiration biopsy (FNAB) was reported as colloid or follicular lesion. They were being treated with L-T4 in doses that
suppressed serum TSH. Their classification as meeting criteria
for SCTox was confirmed at baseline and 3 months later when
they were taking the same dose of L-T4. There were 13 patients with diffuse goiter who were assigned and met the
same criteria for SCTox, with whom we proceeded in the
manner described earlier, but without requirement of FNAB,
and 19 patients who were hypothyroid without goiter who
were under suppressive doses of L-T4 at presentation and,
despite being counseled a reduction of L-T4 dose, 36 months
later still had TSH levels that were suppressed. In the SCToxEndog group, none of the patients was on L-T4, antithyroid
drugs, or amiodarone. The underlying etiology of endogenous SCTox was Graves disease (thyrotropin receptor antibody) (n 6), toxic nodular goiter (n 1), and toxic
multinodular goiter (n 2) or Hashi-thyrotoxicosis (n 3).
SCTox-ExogDTC patients had been under suppressive doses
of L-T4 for a variable period of >3 months. Eighty percent of
this group had a pathological diagnosis of papillary cancer,
whereas only 20% had a follicular type.
There were no significant differences in age or BMI among
the four studied groups. Age and BMI were, respectively,

40.0  10.7 years and 24.8  2.03 for SCTox-ExogG, 36.0  5.44
years and 24.9  2.1 for SCTox-Endog, 40.8  10.5 years and
24.1  2.6 for SCTox-ExogDTC, and 39  10 years and
25.1  2.7 for C.
TSH levels were significantly decreased in all SCTox when
compared with euthyroids. Although total T4, free T4, and T3
levels were within normal parameters, all SCTox groups had
significantly higher hormone levels than the euthyroid group.
The T3/T4 ratio was analyzed and the SCTox-Endog group
showed a significantly higher ratio than SCTox-ExogG and
SCTox-ExogDTC groups ( p < 0.05) (Table 1). L-T4 dose was
120  31 mg/day in the SCTox-ExogG group and 148  35 mg/
day in SCTox-ExogDTC.
Table 2 shows baseline and postprandial blood glucose and
insulin levels as well as IS parameters: HOMA-IR, QUICKI, and
Aloulou indexes and the insulin secretion variable (HOMA-B)
of all groups. All studied parameters were significantly different by ANOVA (Table 2). According to Tukeys post hoc test,
except for HOMA-B and for baseline and postprandial glycemia (only for SCTox-ExogG), the rest of the variables were
significantly different between the SCTox groups and the
control group (Table 3). SCTox-Endog, however, had higher
baseline serum insulin and HOMA-IR and lower QUICKI
levels than the rest of the SCTox groups (Table 3).
The regression analysis suggested a moderate linear relationship between T3 and HOMA-IR in the whole population
(r: 0.54, r2: 0.29, p < 0.0001; Fig. 1). If we excluded DTC patients, the association was stronger (r: 0.66, r2: 0.44,
p < 0.0001).
Discussion
Our findings confirm that SCTox is characterized by lower
IS, as it had been formerly described for overt thyrotoxicosis
(24,25). Further, all types of SCTox share this pattern.
Yavuz et al. (7) have reported that whole-body IS during an
oral glucose tolerance test (OGTT) is significantly decreased in
patients with euthyroid multinodular goiter after 24 weeks of
suppressive doses of L-T4. In line with their findings, we
observed that treatment of nodular goiter or L-T4 overdosage
in hypothyroid patients results in both decreased central and
peripheral glucose sensitivity when compared with euthyroid
controls. Conversely, insulin secretion by pancreatic B-cells is
preserved as reflected by similar HOMA-B levels between the
groups.
With regard to SCTox in thyroid cancer patients, all IS
parameters were also in a deteriorated state in comparison

948

REZZONICO ET AL.
Table 2. Metabolic Parameters (Mean  Standard Deviation and p-Values of Analysis of Variance)

Variable

ANOVA p-value

SCTox-ExogG

SCTox-Endog

SCTox-ExogDTC

0.0020
0.0007
<0.0001
<0.0001
<0.0001
ns
<0.0001
<0.0001

88  9
93  13
94
50  30
2.0  0.9
145  81
0.35  0.03
3.0  0.2

93  9
104  14
15  4b
69  36
3.4  0.9b
191  73
0.32  0.03b
2.9  0.1

91  10
95  13
10  5
56  25
2.1  1.1
154  122
0.35  0.03
3.0  0.1

83  10a
86  16a
6  3a
29  20a
1.2  0.7a
140  101
0.38  0.01a
3.3  0.4a

Baseline glycemia, mg/dL

Postprandial glycemia, mg/dL
Baseline insulinemia, mIU/mL
Postprandial insulinemia, mIU/mL
HOMA-IR
HOMA-B
QUICKI
Aloulou
a

p < 0.05 between the control group and the SCTox groups by Tukey post hoc analysis.
p < 0.05 between the SCTox-Endog group and the rest of the SCTox groups by Tukey post hoc analysis.
HOMA-IR, homeostasis model assessment of insulin resistance; QUICKI, quantitative insulin sensitivity check index; ns, not significant.
b

with the euthyroid group. In contrast, Heemstra et al. (9)

found that restoration to euthyroidism in DTC patients with
previous L-T4-induced SCTox had no influence on glucose
metabolism. They postulated that long-term L-T4 treatment
(>10 years) can bring along an adaptative state. This concept
of adaptation is not consistent with our previous observation
in DTC patients in whom the proportions of IR (defined as
HOMA-IR >2.5) at diagnosis and several years (>5) thereafter
were similar (10). An alternative explanation, both to their
negative findings within a group of DTC with differential
treatment and also to our results in the present study, is that
some thyroid cancer patients may be insulin resistant per se
and not only as a consequence of L-T4 treatment. In support of
this idea we found that, after excluding DTC patients, the
association between T3 and HOMA-IR became stronger.
Several lines of research have confirmed that IR is associated
with cancer (26) and that this concept also holds true in DTC
(10,11).
We also found more IR in the SCTox-Endog group of
patients compared with the euthyroid group. No strong

Table 3. Significant Differences at a Level of 5%

by Post Hoc Test of Baseline and Postprandial
Glycemia and Insulinemia, of Insulin Sensitivity
(HOMA-IR, QUICKI, and Aloulou Indexes), and
of Secretion by Pancreatic B-Cells (HOMA-B Index)
Parameters Between Studied Groups
SCTox-ExogG

SCTox-Endog

background for IR studies in endogenous SCTox exists in the

literature. Very recently, however, Maratou et al. (8) reported
that the sensitivity of glucose metabolism in endogenous
subclinical thyrotoxic patients to insulin in vivo (measured by
an OGTT) and in vitro (by measuring insulin-stimulated rates
of glucose transport in isolated monocytes) was lower than a
euthyroid control group. Our results, with a mixed meal test,
a physiologic stimulus to assess insulin secretion and action,
agree with these findings.
Probably, the most interesting aspect of our study is that we
were able to compare the effects on glucose metabolism of
SCTox according to etiology. Although both exogenous and
endogenous SCTox were related to lower IS when compared
with euthyroid condition, it was SCTox-Endog the most affected group. As mentioned earlier, thyrotoxicosis is linked to
IR. According to the higher T3/T4 ratio found in these patients and the moderate linear relationship encountered between T3 and HOMA-IR in the whole population, it could be
hypothesized that the tissues of the patients with endogenous
SCTox were relatively more thyrotoxic.
In conclusion, IR is present in all subclinical thyrotoxic
patients. L-T4 suppressive treatment for nodular goiter and
DTC, or iatrogenic SCTox, can all lead to IR. Endogenous
SCTox is, however, the most delicate situation.

B insulinemia
HOMA-IR
QUICKI

B and Pp
C
B and Pp
glycemia and
insulinemia
insulinemia
HOMA-IR
HOMA-IR
QUICKI
QUICKI
Aloulou
Aloulou
B and Pp
SCToxns
B insulinemia
glycemia and
ExogDTC
HOMA-IR
insulinemia
QUICKI
HOMA-IR
QUICKI
Aloulou
SCToxEndog

B, baseline; Pp, postprandial.

FIG. 1. Linear regression of T3 versus homeostasis model

assessment of insulin resistance for all patients. Observed
values (T3) and predicted values (T3 pred) are plotted.

INSULIN RESISTANCE AND SUBCLINICAL THYROTOXICOSIS

Disclosure Statement
The authors have nothing to disclose.
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Address correspondence to:

Gabriela Brenta, M.D.
Division of Endocrinology
Cesar Milstein Hospital
La Rioja 951
Buenos Aires 1221
Argentina
E-mail: gbrenta@gmail.com