ORIGINAL STUDIES, REVIEWS,

AND SCHOLARLY DIALOGTHYROID FUNCTION AND DYSFUNCTION

The Association of Insulin Resistancewith Subclinical Thyrotoxicosis

Jorge Rezzonico,1 Hugo Niepomniszcze,2 Mariana Rezzonico,1 Eduardo Pusiol,2

Marcelo Alberto,1 and Gabriela Brenta3

Background: Although overt thyrotoxicosis is associated with reduced insulin sensitivity (IS), the effects ofsubclinical thyrotoxicosis (SCTox) (i.e., suppressed serum thyroid-stimulating hormone with free thyroxine andtri-iodothyronine within the reference range) on glucose metabolism are not clear. SCTox may be of endogenousorigin or due to ingestion of supraphysiological amounts of thyroid hormone. Our hypotheses were that reducedIS is present in SCTox and that the degree of reduction differs between SCTox of endogenous and exogenousorigin.Methods: The study population consisted of 125 premenopausal, normal-weight women, divided into fourgroups: exogenous SCTox due to L-T4 treatment for benign goiter or hypothyroidism (SCTox-ExogG) (n¼ 53),endogenous SCTox (SCTox-Endog) (n¼ 12), exogenous SCTox due to L-T4 treatment for differentiated thyroidcancer (SCTox-ExogDTC) (n¼ 20), and finally euthyroid women (C) (n¼ 40) as a control group. After a mixedmeal challenge, glucose and insulin were determined at baseline and 120 minutes later. IS was assessed byhomeostasis model assessment of insulin resistance (HOMA-IR) index, quantitative IS check index (QUICKI),and 2 hours IS Avignon’s index amended by Aloulou for mixed food. Secretion by pancreatic B-cells wascalculated by HOMA-B index. Comparison among groups was done by analysis of variance followed by Tukeytest. 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 higherlevels of insulin (baseline and postmeal) and HOMA-IR and lower values of QUICKI and Aloulou whencompared with controls. SCTox-Endog, however, had higher baseline insulin levels and HOMA-IR and a lowerQUICKI index than the rest of the SCTox groups. Although within the normal range, total T4, free T4, and T3levels were also significantly higher in the SCTox groups than in euthyroids. In SCTox-Endog, T3/T4 ratio wasincreased above the rest of SCTox groups. A moderate linear relationship between T3 and HOMA-IR was foundin the whole population.Conclusions: IR is associated with SCTox of either endogenous or exogenous origin. However, based on ourfindings of lower IS compared with the rest of the SCTox groups, the endogenous subclinical form might have aneven larger metabolic impact.

Introduction

The relationship between thyroid dysfunction andglucose homeostasis has long been studied, with overt

thyrotoxicosis being the epitome of how impaired thyroidfunction can lead to IR. A clear example of this dysregulationin clinical practice is the worsening of glucose control in dia-betics who become hyperthyroid (1). The main alterationsadvocated to explain this phenomenon include increased

endogenous glucose output by the liver, both through a directeffect of T3 on gluconeogenesis (2) and also acting at the hy-pothalamus, increasing functionally reciprocal sympatheticand parasympathetic autonomic outputs to the liver (3). Si-multaneously, an impaired response to insulin stimulation ofmajor intracellular pathways of glucose metabolism in pe-ripheral tissues prevails (4). Although the pathophysiologybehind peripheral IR has not been fully elucidated, a lowerglucose extraction from serum in proportion to increased

Presented as a poster (p-0707) at the 14th International Thyroid Congress, Paris, France, September 11–16, 2010.1Endocrinology Unit, Centro Privado de Endocrinologıa, Mendoza, Argentina.2Division of Endocrinology, Hospital de Clınicas-University of Buenos Aires, Buenos Aires, Argentina.3Division of Endocrinology, Cesar Milstein Hospital, Buenos Aires, Argentina.

THYROIDVolume 21, Number 9, 2011ª Mary Ann Liebert, Inc.DOI: 10.1089/thy.2010.0402

945

blood flow levels in overt hyperthyroid patients has beendemonstrated (5). Moreover, it has been suggested that anincreased secretion of IL6 and TNFa can be implicated in theIR found in peripheral tissues (6).

Subclinical thyrotoxicosis (SCTox) has been also associatedwith IR (7,8) in some but not all studies (9). Part of this con-troversy, despite a common biochemical definition, might liein the heterogeneous nature of SCTox. Although suppressivethyroid-stimulating hormone (TSH) treatment with le-vothyroxine (L-T4) aimed at benign goiter shrinkage is ofuncertain value, exogenous SCTox from this treatment is stillfrequently encountered. On the other hand, some differ-entiated thyroid cancer (DTC) patients do not have anyalternative to L-T4 suppressive treatment. Further, the pre-viously reported (10,11) positive relationship between DTCand IR may add to this lack of consensus. Finally, endogenousSCTox, resulting from longstanding autonomous nodulargoiter or Graves’ disease, also represents a potential source ofIR with an unrecognized clinical impact.

As data about a possible association between SCTox and IRare controversial, we performed a study to look for differencesin insulin sensitivity (IS) among euthyroid subjects, patientswith SCTox of endogenous origin, and patients with goiterand thyroid cancer who had SCTox of exogenous origin.

Materials and Methods

Population

This study included 125 women who were nonobese (bodymass index [BMI] <30), 18–55 years of age, and lived in anarea that was currently iodine sufficient (12). They had con-sulted at our Endocrinology Center at Mendoza in the periodfrom 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, oriodine and women treated at doses below 50 mg per day of L-T4 (13). Women with known diabetes or those with fastingglucose serum levels greater than 125 mg/dL (14) or post-prandial blood glucose greater than 150 mg/dL (15) were alsoexcluded.

The population was divided into four groups: exogenousSCTox due to L-T4 treatment for benign goiter or L-T4 over-dosage (SCTox-ExogG) (n¼ 53), endogenous SCTox (SCTox-Endog) (n¼ 12), exogenous SCTox due to L-T4 treatment for(SCTox-ExogDTC) (n¼ 20), and euthyroid women (C) as acontrol group (n¼ 40). The C group was composed of indi-viduals undergoing evaluation for irregular menses (n¼ 6),health checkup (n¼ 10), pseudogoiter (n¼ 2), friend’s advice(n¼ 5), excessive perspiration (n¼ 4), weight control (n¼ 9),hirsutism (n¼ 2), edema (n¼ 2) who were found to not haveongoing thyroid dysfunction, thyroid autoimmunity, or goi-ter. 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 deter-mined at baseline and 120 minutes later. IS was assessed byhomeostasis model assessment of IR (HOMA-IR) index (16),quantitative IS check index (QUICKI) (17), and 2 hours ISAvignon’s index amended by Aloulou for mixed meal (18,19).Secretion by pancreatic B-cells was calculated by the index ofb-cell function derived from the homeostatic model (HOMA-B) (16).

This study was approved by the ethics committee of ourinstitution. Written informed consent was obtained from allsubjects before initiating the study.

Clinical and biochemical measurements

A clinical history and physical examination that includedanthropometric measurements was performed in all partici-pants. Patients were barefoot when weight and height wereassessed. BMI was calculated as weight over height squared(kg/m2). All study patients had total T4, free T4, T3, TSH, andantithyroperoxidase (ATPO) levels assayed within 7 daysbefore entry into the protocol. To make the diagnosis of goiter,an ultrasonogram was performed and thyroid volume wascalculated. Thyroid volumes larger than 12 mL (20) and mixedor solid nodules larger than 5 or 3 mm in diameter, respec-tively, met the criteria for goiter.

After measuring baseline glucose and insulin levels, astandard mixed breakfast (812 calories, 66% from carbohy-drate, 11% protein, and 22% fat) (15,21,22) was taken by thesubjects. After breakfast the subjects rested until blood glu-cose and insulin were measured again at 2 hours after thismeal. Insulin sensitivity and secretion were calculated usingthe following equations:

HOMA-IR ¼ SG0 · SI0=405

QUICKI ¼ 1=ðlog SG0 þ log SI0ÞHOMA-B ¼ 20 · SI0=ðSG0=18Þ � 3:5

Aloulou index:

2812þ 67 · 105=ðSG2h · SI2hÞ · apparent volume of

distribution of SG ¼ 150 mL · kg body weight

where SG¼ serum glucose (mg/dL) and SI¼ serum insulin(mIU/mL), measured at baseline (0) and 2 hours (2h).

Both QUICK (17) and HOMA-IR (16) are considered sur-rogates of central IS (23) and we used them to assess IR in theliver. Aloulou index, which takes into account the values ofpostprandial glucose and insulin levels, was used to assessperipheral glucose sensitivity (22, 23).

Normal values of postprandial blood glucose were consid-ered to be 112 mg/dL or less. Glucose intolerance was definedby glucose levels of 113–150 mg/dL at 2 hours after the stan-dard mixed breakfast (22). All blood samples were drawn after12 hours of fasting without any medication. Except for thedetermination 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 com-petitive chemiluminescent enzyme immunoassay method insolid phase (IMMULITE�; Siemens, Los Angeles, CA). Re-ference values for total T4 were 4.5–12.5 mg/dL; they were0.7–1.8 ng/dL for free T4 and 90–180 ng/dL for total T3. TSHwas measured with a noncompetitive chemiluminescentenzyme immunoassay method in solid phase (IMMULITE).Reference values for serum TSH were 0.3–4.5 mU/L. ATPOand antithyroglobulin (anti-TG) antibodies were assessed by asequential enzyme immunometric assay chemiluminescentsolid phase (IMMULITE). Reference values were less than20 IU/mL for both TPO and TG antibodies. Insulin wasmeasured by enzyme immunometric assay with a two-sitechemiluminescent solid phase (IMMULITE). Reference valuesfor 2 hours postprandial insulin were less than 10.0 mIU/mL.

946 REZZONICO ET AL.

Glucose was measured by an enzymatic method usingglucose oxidase/peroxidase (Roche Diagnostics, Mannheim,Germany); reference values were 70–110 mg/dL. The mea-surement of glucose was performed in collected plasma fromblood with EDTA/fluoride, so as to avoid errors by enzymaticdestruction of blood glucose (glycolysis).

Statistical analysis

Statistical analysis was performed with SPSS softwarepackage (SPSS, Chicago, IL). Values are presented asmean� SD. Comparison among groups was done by analysisof variance (ANOVA) followed by Tukey test. Transforma-tions were used to achieve homogeneity of variance: ‘‘log’’ inthe case of basal serum insulin and ‘‘ranks’’ for postprandialserum glucose and insulin levels and HOMA-IR, QUICKI,and Aloulou indexes. Weighted least squares were used forTSH and T3/T4. Linear regression analysis of T3 versusHOMA-IR was calculated. Differences were considered sig-nificant at p less than or equal to 0.05.

Results

The SCTox-ExogG group was comprised of 20 patientswith ‘‘multinodular goiter,’’ and of them, fine-needle aspira-tion biopsy (FNAB) was reported as colloid or follicular le-sion. They were being treated with L-T4 in doses thatsuppressed serum TSH. Their classification as meeting criteriafor SCTox was confirmed at baseline and 3 months later whenthey were taking the same dose of L-T4. There were 13 pa-tients with ‘‘diffuse goiter’’ who were assigned and met thesame criteria for SCTox, with whom we proceeded in themanner described earlier, but without requirement of FNAB,and 19 patients who were ‘‘hypothyroid without goiter’’ whowere under suppressive doses of L-T4 at presentation and,despite being counseled a reduction of L-T4 dose, 3–6 monthslater still had TSH levels that were suppressed. In the SCTox-Endog group, none of the patients was on L-T4, antithyroiddrugs, or amiodarone. The underlying etiology of endoge-nous SCTox was Graves’ disease (thyrotropin receptor anti-bodyþ) (n¼ 6), toxic nodular goiter (n¼ 1), and toxicmultinodular goiter (n¼ 2) or Hashi-thyrotoxicosis (n¼ 3).SCTox-ExogDTC patients had been under suppressive dosesof L-T4 for a variable period of >3 months. Eighty percent ofthis group had a pathological diagnosis of papillary cancer,whereas only 20% had a follicular type.

There were no significant differences in age or BMI amongthe four studied groups. Age and BMI were, respectively,

40.0� 10.7 years and 24.8� 2.03 for SCTox-ExogG, 36.0� 5.44years and 24.9� 2.1 for SCTox-Endog, 40.8� 10.5 years and24.1� 2.6 for SCTox-ExogDTC, and 39� 10 years and25.1� 2.7 for C.

TSH levels were significantly decreased in all SCTox whencompared with euthyroids. Although total T4, free T4, and T3levels were within normal parameters, all SCTox groups hadsignificantly higher hormone levels than the euthyroid group.The T3/T4 ratio was analyzed and the SCTox-Endog groupshowed a significantly higher ratio than SCTox-ExogG andSCTox-ExogDTC groups ( p< 0.05) (Table 1). L-T4 dose was120� 31mg/day in the SCTox-ExogG group and 148� 35mg/day in SCTox-ExogDTC.

Table 2 shows baseline and postprandial blood glucose andinsulin levels as well as IS parameters: HOMA-IR, QUICKI, andAloulou indexes and the insulin secretion variable (HOMA-B)of all groups. All studied parameters were significantly differ-ent by ANOVA (Table 2). According to Tukey’s post hoc test,except for HOMA-B and for baseline and postprandial glyce-mia (only for SCTox-ExogG), the rest of the variables weresignificantly different between the SCTox groups and thecontrol group (Table 3). SCTox-Endog, however, had higherbaseline serum insulin and HOMA-IR and lower QUICKIlevels than the rest of the SCTox groups (Table 3).

The regression analysis suggested a moderate linear rela-tionship between T3 and HOMA-IR in the whole population(r: 0.54, r2: 0.29, p< 0.0001; Fig. 1). If we excluded DTC pa-tients, the association was stronger (r: 0.66, r2: 0.44,p< 0.0001).

Discussion

Our findings confirm that SCTox is characterized by lowerIS, 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 anoral glucose tolerance test (OGTT) is significantly decreased inpatients with euthyroid multinodular goiter after 24 weeks ofsuppressive doses of L-T4. In line with their findings, weobserved that treatment of nodular goiter or L-T4 overdosagein hypothyroid patients results in both decreased central andperipheral glucose sensitivity when compared with euthyroidcontrols. Conversely, insulin secretion by pancreatic B-cells ispreserved as reflected by similar HOMA-B levels between thegroups.

With regard to SCTox in thyroid cancer patients, all ISparameters were also in a deteriorated state in comparison

Table 1. Thyroid Status (Mean� Standard Deviation)

Variable ANOVA p-value SCTox-ExogG SCTox-Endog SCTox-ExogDTC C

T4 <0.0001 10.48� 1.44 10.31� 1.73 10.50� 1.51 7.28� 1.31a

Free T4 0.0004 1.42� 0.27 1.53� 0.19 1.53� 0.27 1.12� 0.19a

T3 <0.0001 135� 19 150� 16 138� 19 113� 13a

TSH <0.0001 0.16� 0.10 0.15� 0.13 0.12� 0.11 1.99� 0.73a

T3/T4 <0.0001 12.21� 1.47 14.45� 0.76b 12.99� .48 13.97� 3.23

ap< 0.05 between the control group and the SCTox groups by Tukey post hoc analysis.bp< 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 differentiatedthyroid cancer; C, euthyroid women; ANOVA, analysis of variance.

INSULIN RESISTANCE AND SUBCLINICAL THYROTOXICOSIS 947

with the euthyroid group. In contrast, Heemstra et al. (9)found that restoration to euthyroidism in DTC patients withprevious L-T4-induced SCTox had no influence on glucosemetabolism. They postulated that long-term L-T4 treatment(>10 years) can bring along an adaptative state. This conceptof adaptation is not consistent with our previous observationin DTC patients in whom the proportions of IR (defined asHOMA-IR>2.5) at diagnosis and several years (>5) thereafterwere similar (10). An alternative explanation, both to theirnegative findings within a group of DTC with differentialtreatment and also to our results in the present study, is thatsome thyroid cancer patients may be insulin resistant per seand not only as a consequence of L-T4 treatment. In support ofthis idea we found that, after excluding DTC patients, theassociation between T3 and HOMA-IR became stronger.Several lines of research have confirmed that IR is associatedwith cancer (26) and that this concept also holds true in DTC(10,11).

We also found more IR in the SCTox-Endog group ofpatients compared with the euthyroid group. No strong

background for IR studies in endogenous SCTox exists in theliterature. Very recently, however, Maratou et al. (8) reportedthat the sensitivity of glucose metabolism in endogenoussubclinical thyrotoxic patients to insulin in vivo (measured byan OGTT) and in vitro (by measuring insulin-stimulated ratesof glucose transport in isolated monocytes) was lower than aeuthyroid 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 wewere able to compare the effects on glucose metabolism ofSCTox according to etiology. Although both exogenous andendogenous SCTox were related to lower IS when comparedwith euthyroid condition, it was SCTox-Endog the most af-fected group. As mentioned earlier, thyrotoxicosis is linked toIR. According to the higher T3/T4 ratio found in these pa-tients and the moderate linear relationship encountered be-tween T3 and HOMA-IR in the whole population, it could behypothesized that the tissues of the patients with endogenousSCTox were relatively more thyrotoxic.

In conclusion, IR is present in all subclinical thyrotoxicpatients. L-T4 suppressive treatment for nodular goiter andDTC, or iatrogenic SCTox, can all lead to IR. EndogenousSCTox is, however, the most delicate situation.

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

Variable ANOVA p-value SCTox-ExogG SCTox-Endog SCTox-ExogDTC C

Baseline glycemia, mg/dL 0.0020 88� 9 93� 9 91� 10 83� 10a

Postprandial glycemia, mg/dL 0.0007 93� 13 104� 14 95� 13 86� 16a

Baseline insulinemia, mIU/mL <0.0001 9� 4 15� 4b 10� 5 6� 3a

Postprandial insulinemia, mIU/mL <0.0001 50� 30 69� 36 56� 25 29� 20a

HOMA-IR <0.0001 2.0� 0.9 3.4� 0.9b 2.1� 1.1 1.2� 0.7a

HOMA-B ns 145� 81 191� 73 154� 122 140� 101QUICKI <0.0001 0.35� 0.03 0.32� 0.03b 0.35� 0.03 0.38� 0.01a

Aloulou <0.0001 3.0� 0.2 2.9� 0.1 3.0� 0.1 3.3� 0.4a

ap< 0.05 between the control group and the SCTox groups by Tukey post hoc analysis.bp< 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.

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 C

SCTox-Endog

B insulinemiaHOMA-IRQUICKI

— —

C B and PpinsulinemiaHOMA-IRQUICKIAloulou

B and Ppglycemia andinsulinemiaHOMA-IRQUICKIAloulou

—

SCTox-ExogDTC

ns B insulinemiaHOMA-IRQUICKI

B and Ppglycemia andinsulinemiaHOMA-IRQUICKIAloulou

B, baseline; Pp, postprandial.

FIG. 1. Linear regression of T3 versus homeostasis modelassessment of insulin resistance for all patients. Observedvalues (T3) and predicted values (T3 pred) are plotted.

948 REZZONICO ET AL.

Disclosure Statement

The authors have nothing to disclose.

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Address correspondence to:Gabriela Brenta, M.D.

Division of EndocrinologyCesar Milstein Hospital

La Rioja 951Buenos Aires 1221

Argentina

E-mail: gbrenta@gmail.com

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