Diabetes Care Volume 42, February 2019 303

Martin Laclaustra,1,2,3,4
Impaired Sensitivity to Thyroid Belen Moreno-Franco,1,2,3
Jose Manuel Lou-Bonafonte,1,5,6
Hormones Is Associated With Rocio Mateo-Gallego,1,2,3
Jose Antonio Casasnovas,1,2,3
Diabetes and Metabolic Syndrome Pilar Guallar-Castillon,7,8,9
Diabetes Care 2019;42:303–310 | https://doi.org/10.2337/dc18-1410 Ana Cenarro,1,2,3 and Fernando Civeira1,2,3

OBJECTIVE
Diabetes prevalence and incidence increase among individuals with hypothyroidism
but also among those with hyperthyroxinemia, which seems contradictory. Both
high free thyroxine (fT4) and high thyroid-stimulating hormone (TSH) are present in
the resistance to thyroid hormone syndrome. A mild acquired resistance to thyroid
hormone might occur in the general population and be associated with diabetes.
We aimed to analyze the association of resistance to thyroid hormone indices
(the Thyroid Feedback Quantile-based Index [TFQI], proposed in this work, and
the previously used Thyrotroph T4 Resistance Index and TSH Index) with diabetes.

RESEARCH DESIGN AND METHODS 1

Instituto de Investigación Sanitaria de Aragón
We calculated the aforementioned resistance to thyroid hormone indices based on (IIS Aragón), Universidad de Zaragoza, Zaragoza,
Spain
a U.S. representative sample of 5,129 individuals ‡20 years of age participating in 2
Translational Research Unit, Hospital Univer-
the 2007–2008 National Health and Nutrition Examination Survey (NHANES). Also, sitario Miguel Servet, Zaragoza, Spain
3
to approximate TFQI, a U.S.-referenced Parametric TFQI (PTFQI) can be calculated CIBERCV, Madrid, Spain
4
with the spreadsheet formula 5NORM.DIST(fT4_cell_in_pmol_per_L,10.075, Fundación Agencia Aragonesa para la Inves-

CARDIOVASCULAR AND METABOLIC RISK

tigación y el Desarrollo (ARAID), Zaragoza, Spain
2.155,TRUE)1NORM.DIST(LN(TSH_cell_in_mIU_per_L),0.4654,0.7744,TRUE)21. 5
Instituto Agroalimentario de Arag ón, CITA-
Outcomes of interest were glycohemoglobin ‡6.5%, diabetes medication, Universidad de Zaragoza, Zaragoza, Spain
6
diabetes-related deaths (diabetes as contributing cause of death), and addi- CIBEROBN, Madrid, Spain
7
tionally, in a fasting subsample, diabetes and metabolic syndrome. Logistic Department of Preventive Medicine and Public
Health, School of Medicine, Universidad Autónoma
and Poisson regressions were adjusted for sex, age, and race/ethnicity. de Madrid-IdiPaz, and CIBERESP, Madrid, Spain
8
IMDEA Food Institute, CEI UAM+CSIC, Madrid,
RESULTS Spain
Odd ratios for the fourth versus the first quartile of TFQI were 1.73 (95% CI 1.32, 2.27)
9
Welch Center for Prevention, Epidemiology,
(Ptrend 5 0.002) for positive glycohemoglobin and 1.66 (95% CI 1.31, 2.10) (Ptrend 5 and Clinical Research, Johns Hopkins University,
Baltimore, MD
0.001) for medication. Diabetes-related death rate ratio for TFQI being above versus
Corresponding author: Martin Laclaustra,
below the median was 4.81 (95% CI 1.01, 22.94) (Ptrend 5 0.015). Further adjustment [email protected]
for BMI and restriction to normothyroid individuals yielded similar results. Per 1 SD Received 2 July 2018 and accepted 4 November
in TFQI, odds increased 1.13 (95% CI 1.02, 1.25) for diabetes and 1.16 (95% CI 1.02, 2018
1.31) for metabolic syndrome. The other resistance to thyroid hormone indices This article contains Supplementary Data online
showed similar associations for diabetes-related deaths and metabolic syndrome. at http://care.diabetesjournals.org/lookup/suppl/
doi:10.2337/dc18-1410/-/DC1.
CONCLUSIONS © 2018 by the American Diabetes Association.
Higher values in resistance to thyroid hormone indices are associated with obesity, Readers may use this article as long as the work
is properly cited, the use is educational and not
metabolic syndrome, diabetes, and diabetes-related mortality. Resistance to
for profit, and the work is not altered. More infor-
thyroid hormone may reflect energy balance problems driving type 2 diabetes. mation is available at http://www.diabetesjournals
These indices may facilitate monitoring treatments focused on energy balance. .org/content/license.
304 Resistance to Thyroid Hormone and Diabetes Diabetes Care Volume 42, February 2019

Recent evidence suggests that hyper- because they can be quantified just approved by the National Center for
thyroxinemia may be cross-sectionally observing thyroid hormones and TSH Health Statistics (NCHS) Research Ethics
and prospectively associated with type 2 concentrations or indices derived from Review Board (Continuation of Protocol
diabetes (1). This is at odds with the them (13,14), although suppression tests no. 2005-06).
physiological metabolism-activating have also been described (15).
action of thyroid hormones, which Thus, given the thyroid feedback loop, Thyroxine, TSH, and Resistance to
is considered capable of ameliorating the aforementioned reports showing Thyroid Hormone Indices
obesity-related morbidities (2). It is association of high thyroid hormones Free thyroxine (fT4) was quantified with
also in conflict with the increased in- or high TSH with the prevalence and the Access Free T4 assay, a two-step
cidence of diabetes reported among incidence of metabolic syndrome and enzyme immunoassay, and TSH was quan-
patients with hypothyroidism (3) and diabetes provide apparently contradict- tified with the Access HYPERsensitive
with the increased prevalence of met- ing results. In this work, we hypothesized hTSH Assay, a two-site immunoenzymatic
abolic syndrome described in the that these conflicting results might be (“sandwich”) assay. Measurements were
upper-normal range of the pituitary conciliated if high thyroid hormones and performed at the University of Washing-
thyroid-stimulating hormone (TSH) (also high TSH co-occurrence in diabetes re- ton (Seattle, WA). The laboratory normality
known as thyrotropin) (4), a range as- flected a central resistance to thyroid reference ranges were 7.74–20.64 pmol/L
sociated with lower thyroid activity. Pre- hormone. If that were the case, this for fT4 and 0.34–5.60 mIU/L for TSH.
vious evidence is inconsistent (4): some central resistance would probably be Thyrotroph T4 Resistance Index (TT4RI)
studies find diabetes or metabolic syn- the expression of a general reduced sen- was calculated as fT4 (pmol/L) z TSH
drome to be associated with TSH but not sitivity to thyroid hormones, i.e., not only (mIU/L) (13). TSH index (TSHI) was cal-
with thyroid hormones, whereas others central but also peripheral. This resistance culated as ln TSH (mIU/L) + 0.1345 z fT4
find an association only with thyroid hor- to thyroid hormone could be one addi- (pmol/L) (14).
mones, occasionally linking opposite tional characteristic of the cardiome-
ends of the thyroid hormone concen- tabolic traits predicting diabetes. We TFQI, a New Resistance to Thyroid
tration range with diabetes. The effect analyzed continuous National Health Hormone Index
of thyroid hormones on insulin sensitiv- and Nutrition Examination Survey Given encouraging preliminary results
ity differs by tissue; it enhances glu- (NHANES) (16) data to gain insight from the description of participants
cose uptake in the muscle but reduces into this issue and propose the Thyroid who were simultaneously in the extreme
it in the liver (5). The overall net effect Feedback Quantile-based Index (TFQI), quartiles of fT4 and TSH (see STATISTICAL
in hypothyroidism favors insulin resis- a new resistance to thyroid hormone ANALYSES and RESULTS sections), we developed
tance, but in hyperthyroidism it may index focused on deviations close to a new index to quantify, in a continuous
also occasionally favor glucose intoler- normality. manner, deviations from the median pi-
ance (5). These metabolic mechanisms tuitary response (inhibition) to thyroid
described in clinical thyroid diseases hormones: the TFQI, which stands for
may not be enough to explain the asso- RESEARCH DESIGN AND METHODS thyroid feedback quantile-based index.
ciations found within the normothyroid Design and Participants Ranks (order position from minimum
range. Thyroid hormones and TSH were mea- to maximum value) of fT4 and TSH were
Physiologically, thyroid hormones and sured in serum in 5,222 (N1) adults converted to quantiles between 0 and 1,
TSH are inversely correlated owing to a 20 years of age and older in the con- taking into account sampling weights.
negative feedback loop. However, high tinuous NHANES (16) performed in Fractional quantiles are a generalization
thyroid hormones coexist with high TSH 2007 and 2008, which recruited a rep- that summarizes in a single fraction the
in individuals with resistance to thyroid resentative sample of the noninstitu- ordering number of each part in the
hormone syndrome, an inherited auto- tionalized U.S. population. Data on sequence and the number of parts,
somal recessive trait (6–8). Yet, a possibly mortality up to 2011 from the National e.g., the upper limit of the second tertile
reversible acquired resistance to thyroid Death Index are available for all but six is the value of the quantile 0.66 and
hormone, due to homeostatic compen- individuals. The current study estimates the upper limit of the third quartile is
sation, has been hypothesized (9). Pro- cross-sectional associations between the value of the quantile 0.75. That
longed fasting produces drops in TSH and resistance to thyroid hormone indices conversion is achieved by applying the
increases in pituitary sensitivity to thyroid and diabetes-related conditions as well population empirical cumulative distri-
hormones (10,11). In contrast, morbidly as longitudinal associations between bution function (cdf) to hormone con-
obese individuals tend to have higher the indices and the diabetes-related centration. TFQI was calculated as cdf
levels of both thyroid hormones and mortality rate. Analyses were performed fT4 2 (1 2 cdf TSH), i.e., the difference
TSH (12). Resistance to thyroid hormone using the entire NHANES data set (N1) and between fT4 quantile and the reversed
manifestations can be systematized into several subsets (main complete case sam- TSH quantile, because they are inversely
central resistance phenomena, which ple, N2 = 5,129; normothyroid sample, correlated in the negative feedback loop.
affect the feedback loop set point in the N3 = 4,750; and fasting normothyroid This index ranges between 21 and 1.
central nervous system, and peripheral sample, N4 = 1,997) (see flowchart in Negative values indicate lower TSH
resistance phenomena, which decrease Supplementary Data). NHANES partici- (higher inhibition by fT4) than that
hormones’ metabolic effects. The for- pants provided written informed consent expected for the actual fT4 (which
mer are easier to evaluate than the latter to participate in the survey, which was means higher sensitivity to fT4). Similarly,
care.diabetesjournals.org Laclaustra and Associates 305

positive values indicate higher TSH (lower i.e., diagnosis was issued when meeting indices, this outcome was compared
inhibition by fT4) than that expected for three of the following criteria: 1) waist between values above and below the
the actual fT4 (lower sensitivity to fT4). circumference $102 cm in men or $88 median, and trend was tested with each
Median TSH response to fT4 is represented cm in women; 2) triglycerides $150 mg/dL; index as a continuous variable.
by the value 0. This index is more stable 3) HDL cholesterol ,40 mg/dL in men In the main sample and the normo-
than TT4RI and TSHI at abnormal ranges or ,50 mg/dL in women; 4) systolic or thyroid sample, interquartile compari-
of the thyroid gland responsiveness to diastolic blood pressure $130 mmHg sons were performed for BMI, obesity,
TSH. That is, TFQI does not reach extreme or $85 mmHg, respectively (or receiv- HbA1c $6.5%, diabetes medication use,
values in individuals with thyroid gland– ing medication for hypertension); and 5) and diabetes-related mortality. BMI was
caused (primary) clinical hyper- or hypo- glucose $100 mg/dL (or receiving med- modeled with linear regression; obesity,
thyroidism (see data points in the top-left ication for diabetes). HbA1c $6.5%, and diabetes medication
and bottom-right areas of TSH versus were modeled with logistic regression,
fT4 scatterplots in Supplementary Fig. 1). Mortality and death was modeled with Poisson
In order to provide an index that can be Survey data were linked with the Na- regression.
calculated for any new value or adapted tional Death Index by the NCHS. Besides In the fasting subsample, ORs for di-
to other populations, an approximation the leading cause of death, records also abetes, metabolic syndrome, and meta-
with the same range and interpretation, include contributing causes of death in a bolic syndrome criteria were calculated
the Parametric Thyroid Feedback Quantile- 20 entity axis set of codes for multiple for 1-SD increase of resistance to thyroid
based Index (PTFQI) can be obtained causes of death. The public use linked hormone indices except for TT4RI. This
from fT4 in pmol/L and TSH in mIU/L mortality data set provided by the NCHS index was analyzed using the logarithmic
using the standard normal cumulative includes a flag variable for diabetes when scale, and its OR was calculated for a
distribution function as follows: ICD-10 codes E10–E14 appear as one of TT4RI multiplicative increase by an
F((fT4 2 mfT4)/sfT4) 2 (1 2 F((ln TSH 2 the 20 contributing or multiple causes of SD equivalent (3 2SD log2 TT4RI). Diabetes,
mln TSH)/sln TSH)), where mfT4 = 10.075, death. We used this flag, i.e., diabetes- metabolic syndrome, and metabolic
sfT4 = 2.155, mln TSH = 0.4654, and sln TSH = related death, as our end point. syndrome criteria were modeled with
0.7744 for the U.S. population. This logistic regression.
can be easily achieved with the Excel Statistical Analyses As part of sensitivity analyses, we
or LibreOffice spreadsheet formula Mean and SD of thyroid parameters were further adjusted models for education
=NORM.DIST(fT4_cell,10.075,2.155,TRUE)+ calculated for population sex, age, and level, physical activity performed at work
NORM.DIST(LN(TSH_cell),0.4654,0.7744, race strata. TSH and TT4RI were processed or during leisure time, and daily seden-
TRUE)21. in the logarithmic scale given their skewed tary time. All analyses were performed
distributions. We created scatterplots of with statistical computing software R
Other Variables TSH versus fT4 and plotted population- (18), version 3.4.4, with the package
Demographic (including race/ethnicity based percentiles of the indices. “survey” (19) to account for the NHANES
as nonhispanic white, nonhispanic black, The interesting results observed when complex survey design.
and other), clinical interview, physical we compared participants who were
examination, and other laboratory var- either at the lowest or at the highest
iables were obtained following protocols quartiles of fT4 and TSH simultaneously RESULTS
available in NHANES operation manuals (see Supplementary Data and RESULTS) led The 5,222 participants in the sample
(16). Briefly, glucose was measured with us to develop TFQI and PTFQI (described represented the U.S. population 20 years
the glucose oxidase method and glyco- above). These indices enabled us to study of age and older, and they had a mean
hemoglobin (HbA1c) on the A1c G7 HPLC pituitary feedback response with a con- (SD) age of 46.9 (16.6) years (Table 1).
Glycohemoglobin Analyzer (Tosoh Medics, tinuous variable. Indices of resistance to thyroid hormone
Inc., San Francisco, CA). Blood was We created population-based quar- were higher among older people and
drawn from participants who were vis- tiles for each resistance to thyroid hor- lower among black individuals (Table 1).
ited at any time throughout the day, mone index (TFQI, PTFQI, TT4RI, and In a preliminary analysis, obesity prev-
except for a subsample of participants TSHI). Differences, odds ratios (ORs), alence and, especially, HbA1c $6.5% and
appointed for a morning visit and re- and rate ratios (RRs) across quartiles, use of diabetes medication showed a
quested to fast. In the main sample data using the lowest as reference, were tendency to be higher among partici-
set (which includes nonfasting data), high estimated with generalized linear, logis- pants whose fT4 and TSH were simulta-
HbA1c ($6.5%, i.e., $48 mmol/mol) and tic, and Poisson regression models, re- neously above their 75th percentiles
use of diabetes medication were ana- spectively. Model 1 adjusted for sex, age, (Supplementary Data).
lyzed, as they can be interpreted as and race. Model 2 further adjusted for A scatterplot of TSH versus fT4 shows
proxies for diabetes. In the fasting sub- BMI. Model 3 further adjusted for initially the negative correlation of these varia-
sample, diabetes was defined as fasting presenting HbA1c $6.5% and diabetes bles, while the contour lines show se-
($8 h) glycemia $126 mg/dL or present- medication use. For each trend, signifi- lected percentiles for each one of the
ing the previously mentioned proxies. cance was tested with each index quartile resistance to thyroid hormone indices
Obesity was defined as a BMI $30 kg/m2. ordinal as a continuous variable. Given (Fig. 1 and Supplementary Fig. 1).
Metabolic syndrome diagnosis was estab- that there were no diabetes-related TT4RI and TSHI (Supplementary Fig. 1)
lished using the harmonized criteria (17); deaths within the first quartile of three take extreme values (.95th and ,5th
306 Resistance to Thyroid Hormone and Diabetes Diabetes Care Volume 42, February 2019

Table 1—Characteristics and thyroid parameters of the U.S. population represented in the NHANES sample (N1 = 5,222)
% fT4 P TSH* P TFQI P TT4RI* P TSHI P
All 10.08 (2.15) 1.59 0.00 (0.37) 15.73 1.82 (0.74)

Male 48.3 10.04 0.431 1.62 0.220 0.00 0.403 16.02 0.147 1.83 0.299
Female 51.7 10.11 1.57 20.01 15.47 1.81

$20 years and ,40 years 37.0 10.00 ,0.001 1.47 ,0.001 20.05 ,0.001 14.41 ,0.001 1.73 ,0.001
$40 years and ,60 years 39.3 9.80 1.64 20.03 15.79 1.81
$60 years 23.7 10.67 1.72 0.13 17.96 1.98

White 70.7 10.06 0.234 1.69 ,0.001 0.02 ,0.001 16.68 ,0.001 1.88 ,0.001
Black 10.0 9.91 1.19 20.17 11.51 1.51
Other 19.3 10.22 1.49 20.01 14.95 1.77
Data are percentages or means (SD) unless otherwise indicated. P values are for differences between groups and were calculated from linear
regression models. *Calculated as geometric means.

percentile) for almost all patients diag- mentioned associations and provided progressively higher across TFQI quar-
nosed with clinical hypo- and hyperthy- more moderate values among patients tiles after adjustment for sex, age, and
roidism. This seemingly inappropriate with clinical thyroid gland–caused (primary) race (all P , 0.01). ORs of the fourth
result together with our observation disease is what led us to develop TFQI. versus the first TFQI quartile for
that a quantile-based approach (Supple- BMI, obesity prevalence, HbA1c $ 6.5%, HbA1c $6.5% and use of diabetes med-
mentary Data) uncovered the above- and use of diabetes medication were ication were 1.73 (95% CI 1.32, 2.27) and
100

TFQI = cdf fT4 − ( 1 − cdf TSH )

10

P95 P
25
P75 P95
P50 P5
TSH (mIU/L)

P25 P75
1

TFQI interval
P5 300 −P5 P5−P25 P25−P50 P50−P75 P75−P95 P95−

250 Diabetes−related mortality (crude rate)

200 (white dots)
0.1

150
100
50
0
0 0 38 108 205 285
0.01

deaths per 105 person−years

0.001

P5
P5
P25
P50
P75
P95

0 10 20 30 40 50 60

fT4 (pmol/L)
Figure 1—Scatterplot of TSH versus fT4 and bar plot of crude diabetes-related death rates across intervals of TFQI in the NHANES sample
(N1 = 5,222). Scatterplot: dots represent observations. White dots represent participants who died during follow-up and whose deaths were diabetes
related. Gray dashed vertical and horizontal straight lines mark fT4 and TSH normality ranges. Inner marks in the axes represent the 5th, 25th,
50th, 75th, and 95th percentiles of fT4 and TSH. TFQI was calculated for each observation, and its value grows gradually across the plot area, from the
lower-left corner to the upper-right corner. Black dashed curves represent the 5th, 25th, 50th, 75th, and 95th percentiles of TFQI. Inner plot: the bars
and the number at the base show crude death rates for each TFQI interval (percentile ,5, 5–25, 25–50, 50–75, 75–95, and $95) in deaths per 105
person-years. The widths of the bars are proportional to the fraction of the population at risk in each bar so that the area of the bar is proportional
to the absolute number of deaths (i.e., the count of white dots in the scatterplot). cdf, empirical cumulative distribution function; fT4, free thyroxine;
TFQI, Thyroid Feedback Quantile-based Index; TSH, thyroid-stimulating hormone.
care.diabetesjournals.org Laclaustra and Associates 307

Table 2—Association of TFQI with BMI, obesity, high HbA1c, use of diabetes medication, and diabetes-related deaths in the
main sample (N2 = 5,129)
Thyroid Feedback Quantile-based Index (TFQI)
Quartile 1 Quartile 2 Quartile 3 Quartile 4
[$21 and ,20.25) [$20.25 and ,0) [$0 and ,0.25) [$0.25 and #1) Ptrend
N 1,319 1,259 1,270 1,281
2
BMI (kg/m ) 28.1 28.0 29.0 28.8
Model 1, difference (95% CI) 0.0 (Reference) 0.1 (20.6, 0.7) 1.1 (0.7, 1.5) 0.9 (0.1, 1.6) 0.006

Obesity (%) 31.0 29.0 36.7 35.8

Model 1, OR (95% CI) 1.00 (Reference) 0.93 (0.76, 1.14) 1.34 (1.17, 1.54) 1.29 (1.11, 1.50) 0.001

HbA1c $6.5% (%) 5.0 6.4 8.9 10.0

Model 1, OR (95% CI) 1.00 (Reference) 1.28 (0.96, 1.71) 1.70 (1.37, 2.12) 1.73 (1.32, 2.27) 0.002
Model 2, OR (95% CI) 1.00 (Reference) 1.19 (0.91, 1.54) 1.38 (1.06, 1.78) 1.43 (1.07, 1.92) 0.034

Diabetes medication (%) 4.8 7.2 9.2 9.9

Model 1, OR (95% CI) 1.00 (Reference) 1.46 (1.00, 2.13) 1.72 (1.21, 2.44) 1.66 (1.31, 2.10) 0.001
Model 2, OR (95% CI) 1.00 (Reference) 1.36 (0.96, 1.94) 1.41 (1.00, 1.98) 1.39 (1.10, 1.75) 0.028

Diabetes-related deaths (n) 0 4 7 16

Crude rate (per 100,000 person-years) 0.0 38.9 108.9 211.3
Crude rate (per 100,000 person-years) 19.5 159.2
Model 1, RR (95% CI) 1.00 (Reference) 4.81 (1.01, 22.94) 0.015#
Model 2, RR (95% CI) 1.00 (Reference) 3.92 (0.88, 17.51) 0.035#
Model 3, RR (95% CI) 1.00 (Reference) 3.51 (0.78, 15.85) 0.099#
Differences, ORs, and RRs (rate ratios) are estimated with generalized linear, logistic, and Poisson regression models, respectively. Model 1 is adjusted
for sex, age, and race. Model 2 is further adjusted for BMI. Model 3 is further adjusted for initially presenting HbA1c $6.5% and using diabetes
medication. Ptrend is calculated with the TFQI quartile ordinal as a continuous variable except in the models with only two categories in which it is
calculated with TFQI as a continuous variable. #Ptrend for TFQI as a continuous variable.

1.66 (1.31, 2.10), respectively, and the 3 years and 11 months, during which and race-adjusted RR for diabetes-
association was independent of BMI, there were 27 deaths with diabetes related death was 4.81 (95% CI 1.01,
given that after adjustment, OR estima- listed within the entity axis codes for mul- 22.94). TFQI was linearly associated with
tions were only partially reduced to tiple causes of death. In nine of these the rate for diabetes-related death (P =
1.43 (1.07, 1.92) and 1.39 (1.10, 1.75), cases, diabetes was the leading cause of 0.015), and the association remained
respectively (Ptrend ,0.05) (Table 2). death. For participants with TFQI above statistically significant even after adjust-
Participants had a median follow-up of the median (versus below it), sex-, age-, ment for BMI (P = 0.035). One-fourth of

Table 3—ORs (95% CI) of diabetes, metabolic syndrome, and metabolic syndrome criteria for 1-SD increase of TFQI,
PTFQI, and TSHI or multiplication by an SD equivalent of TT4RI in the fasting normothyroid sample (N4 = 1,997)
TFQI (+1 SD) PTFQI (+1 SD) TT4RI (3 2SD log2 TT4RI
) TSHI (+1 SD)
Diabetes 1.13 (1.02, 1.25) 1.13 (1.02, 1.25) 1.09 (0.89, 1.33) 1.10 (0.93, 1.31)
P 0.041 0.036 0.420 0.299
Metabolic syndrome 1.16 (1.02, 1.31) 1.16 (1.03, 1.31) 1.30 (1.09, 1.56) 1.28 (1.09, 1.50)
P 0.040 0.031 0.014 0.013
Waist criterion 0.99 (0.88, 1.11) 0.99 (0.89, 1.11) 1.06 (0.91, 1.24) 1.05 (0.91, 1.21)
P 0.814 0.870 0.439 0.536
Triglyceride criterion 1.07 (0.88, 1.30) 1.07 (0.88, 1.29) 1.40 (1.16, 1.69) 1.33 (1.10, 1.61)
P 0.510 0.506 0.005 0.013
HDL criterion 1.21 (1.05, 1.39) 1.21 (1.06, 1.38) 1.21 (1.04, 1.40) 1.22 (1.06, 1.41)
P 0.024 0.018 0.034 0.021
Blood pressure criterion 1.18 (1.04, 1.34) 1.19 (1.06, 1.35) 1.22 (1.07, 1.38) 1.21 (1.08, 1.37)
P 0.023 0.016 0.013 0.008
Glycemia criterion 1.06 (0.94, 1.20) 1.06 (0.94, 1.19) 1.08 (0.88, 1.32) 1.07 (0.90, 1.28)
P 0.364 0.371 0.472 0.461
ORs are estimated with generalized logistic regression models adjusted for sex, age, and race (model 1) for the increase of 0.37 units TFQI, 0.33 units
PTFQI, and 0.74 units TSHI (1 SD) and for the multiplication of TT4RI by 2.1 (1 SD equivalent). Indices enter the models as continuous
variables. TT4RI enters the model as base 2 log so that the regression coefficient is for each duplication of its value. ORs are comparable across
columns in terms of influence of the index variation on the outcome prevalences.
308 Resistance to Thyroid Hormone and Diabetes Diabetes Care Volume 42, February 2019

deaths occurred among participants hyperthyroxinemia (1) but also call for diabetes onset in a previously meta-
without initial presence of proxies for a new interpretation of thyroid hor- bolically normal individual.
diabetes. However, in spite of a similar mone changes associated with diabetes. Besides secretion regulation by the
magnitude of association for being above As far as we are aware, this is the first hypothalamic-pituitary-thyroid axis, thy-
the median, RR 3.51 (0.78, 15.85), such a time that indices of resistance to thy- roid hormone action is modulated (6,26)
small number of events made it impos- roid hormone have been evaluated in at cell membrane transport, enzymatic
sible to detect a statistically significant the general population and associated modification into active and inactive
association after adjustment for the ini- with cardiometabolic health charac- species by deiodinases, and nuclear re-
tial condition. All results were similar in teristics. Our analyses showed that ceptors. Nutritional signals can modulate
examination of PTFQI instead of TFQI TT4RI and TSHI indices seemed to sys- the thyroid system during some of the
(Supplementary Data). Adjustment for tematically classify thyroid gland–caused regulation, secretion, and action steps.
education, physical activity, and sed- (primary) hypothyroidism and hyper- Hypothalamic neurons inhibit secretion
entary time did not substantially thyroidism (clinical and subclinical) as when leptin levels fall, providing a system
change these results (Supplementary resistant or very sensitive to thyroid to protect against starvation (27). Mean-
Data). hormones, respectively. Thus, we pro- while, an increase in leptin derived from
TT4RI and TSHI were cross-sectionally posed a new index, TFQI. TFQI is based adipose tissue accumulation may indi-
associated with obesity, although not on the empirical joint distribution of cate availability of energetic substrates,
with diabetes proxies. Nonetheless, fT4 and TSH with the advantage of not and, thus, the subsequent activation of
both were prospectively associated yielding extreme values in cases of thy- the thyroid axis could also be interpreted
with diabetes-related mortality inde- roid gland dysfunction. Its parametric as a homeostatic regulation. Accordingly,
pendently of initial presence of diabe- version (PTFQI) can readily be used high TSHdwithin normal levelsdis as-
tes proxies (Supplementary Data). All of as a formula to calculate the index for sociated with increased adiposity (28)
these results persisted in the normothy- any particular individual with reference and consistent with near-hypothyroidism
roid subsample (Supplementary Data) to the U.S. population, or it can be hormonal end effects. This can be inter-
with the exception of RR for mortality. adapted to other reference populations. preted as a deficient thyroid hormone
Although the magnitudes for its indica- All these resistance to thyroid hor- production in relative terms, unable to
tors were very similar, they failed to mone indices measure central sensitiv- meet the metabolic increase required
reach statistical significance, probably ity/resistance, i.e., the grade of pituitary to compensate and avoid more fat ac-
due to the statistical loss of power gland inhibition by fT4 levels. Thus, they cumulation. Interestingly, in morbidly
caused by excluding two deceased par- evaluate the set point of the central obese individuals thyroid hormones are
ticipants who had marginally subclinical regulation of thyroid hormone concen- also elevated (12), hinting at a down-
hypothyroidism (Fig. 1 and Supplemen- tration. Among participants with high stream signal problem. Activity of de-
tary Data). values, peripheral resistance could also iodinases (29), epigenetic modification
We tested cross-sectional associations be present because, despite higher fT4, of histones, and interaction with signal-
of the indices with diabetes and meta- we find in this group higher prevalence ing of other transcription factors (30)
bolic syndrome in the fasting subsam- of obesity, diabetes, and metabolic syn- also regulate, at the cellular level, thy-
ple of normothyroid participants. Only drome, phenotypes usually associated roid hormone actions on metabolism. In
TFQI (and its approximation, PTFQI) with hypothyroidism. addition, in obesity a steady consump-
was associated with diabetes based on Thyroid hormones increase energy tion of high-calorie foods may even
glycemia, HbA 1c, and medication. All expenditure and thermogenesis (20), in- overpower the thyroid stimulus that
resistance to thyroid hormone indices crease glucose and fatty acid oxidation in increases resting metabolic rate (31),
were associated with metabolic syndrome muscle (21) and the liver (22), increase leading to a biochemical phenotype
in general and with HDL and blood pres- adipose tissue lipolysis (23), and promote compatible with an apparent resistance
sure metabolic syndrome criteria. Lastly, lower body weight (24). In sum, they have to thyroid hormone. We previously pro-
TT4RI and TSHI were also associated an overall effect on metabolism that posed a similar interpretation for the
with triglyceride criterion (Table 3). would prevent diabetes development. origin of insulin resistance in obesity (32).
Interestingly, thyroid hormones also sen- From a clinical point of view, there
CONCLUSIONS sitize to catecholamines, which increase seems to be a gradient of increasing
Based on a sample representative of the liver hepatic glycogenolysis, neogluco- thyroid hormones levelsdwithin the
U.S. population, we provide evidence genesis, and glucose output (25); reduce normal rangedacross early stages of
of the association between indices insulin anabolic actions in the liver; and diabetes (33). Furthermore, prospec-
measuring resistance to thyroid hor- increase glucose intestinal absortion (5), tively, higher levels of thyroid hormones
mone and prevalence of obesity, diabe- though the latter effect plays a minor role are associated with incident diabetes (1)
tes, and metabolic syndrome as well as in glucose level derangement. In overt in spite of the fact that hypothyroidism
between these indices and the incidence hyperthyroidism, these changes could is the disorder that clearly increases
of diabetes-related deaths. These associ- be responsible for decompensation of diabetes risk (3). As resistance to thyroid
ations were also identified within the preexisting diabetes and even trigger hormone is one of the differential di-
normal fT4 and TSH ranges. These results ketoacidosis (25), but they may be less agnoses when both fT4 and TSH are
not only reconcile previous reports linking important within the normal range of elevated (34), our results offer an expla-
diabetes to hypothyroidism (3) and to thyroid hormones and unlikely to cause nation for thyroid profiles commonly
care.diabetesjournals.org Laclaustra and Associates 309

found in patients with diabetes. That is, at results between cross-sectional associa- diabetes morbidity and mortality were
the population level, measurements of tions and longitudinal mortality analyses independent of obesity. We propose the
resistance to thyroid hormone are cross- support our conclusions. However, some new TFQI to identify mild levels of ac-
sectionally associated with diabetes, in- limitations exist. Indices of resistance to quired resistance in the general popula-
dependently of the degree of obesity as thyroid hormone increase markedly with tion. Type 2 diabetes is in part driven by
measured with BMI, suggesting that aging. Whereas all analyses are adjusted an energy balance problem, and the
there might be other underlying mech- for age and other potential confound- associated central resistance measured
anisms linking diabetes and resistance to ers, some residual confounding may by indices of resistance to thyroid hor-
thyroid hormone. Furthermore, prospec- remain. Given that many factors may mone may be the result of the physiologic
tively, these measurements were also be associated with diabetes and meta- contraregulation against it. These indices
associated with diabetes-related deaths, bolic syndrome, it is not possible to may facilitate the monitoring and eval-
even independently of the initial diabetes adjust for unavailable variables and un- uation of new therapies that focus on
status. known factors, and the potential re- energy expenditure.
Measurements of resistance to thy- sidual confounding must be considered
roid hormone were also cross-sectionally when interpreting the study results.
associated with metabolic syndrome on One antidiabetes oral agent, metformin, Funding. The research activity of M.L. is funded
a consistent basis. Previous attempts to lowers TSH (leaving fT4 unchanged) by Agencia Aragonesa para la Investigación y el
Desarrollo (ARAID). This work was supported by
relate metabolic syndrome with the thy- among patients with hypothyroidism
grants PI14/00009 and PI17/01709 from Insti-
roid axis either showed an association (37), and there is some evidence hinting tuto de Salud Carlos III (Ministry of Science,
with TSH but not with fT4 (35) or yielded that it sensitizes the pituitary gland and Innovation and Universities), and cofunded by
inconsistent results. We hypothesized peripheral tissues to thyroid hormone European Regional Development Fund/Euro-
that whereas a metabolic status with action (40). Thus, our results may un- pean Social Fund “Investing in your future.”
None of the funding sources had any role in
excess energy may stimulate the thyroid derestimate the true association be- the writing of the manuscript or the decision to
axis, the thyroid boost to energy expen- tween resistance to thyroid hormone submit it for publication.
diture fails to compensate. This results in and diabetes; i.e., the association may Duality of Interest. No potential conflicts of
an expression compatible with resistance be even stronger than the statistically interest relevant to this article were reported.
to thyroid hormone. Thyroid stimuli significant association reported here. Author Contributions. M.L. conceptualized
the research question and designed the study.
still increase, although insufficiently, the Because our analysis focused on resis- M.L. and B.M.-F. performed the statistical data
uncoupled thermogenic oxidative pro- tance to thyroid hormone indices, which analysis. M.L., B.M.-F., J.M.L.-B., and F.C. inter-
cesses, which can be observed as an are all fT4 based, fT3 was intentionally preted the results. M.L. and B.M.-F. wrote the
increase of oxidative stress in metabolic excluded from the models, since it was manuscript. R.M.-G., J.A.C., P.G.-C., A.C., and F.C.
syndrome (36). A sustained compensa- revised the manuscript for important intellec-
considered to be downstream in the
tual content. M.L., B.M.-F., J.M.L.-B., R.M.-G.,
tory TSH stimulus could also explain, in action pathway. Actually, deiodinases J.A.C., P.G.-C., A.C., and F.C. approved the final
part, the recently reported association of balance may play a role in the modulation version of the manuscript for publication. M.L.
metabolic syndrome, insulin resistance, of sensitivity to thyroid hormones (29), is the guarantor of this work and, as such, had
and diabetes with thyroid enlargement, and future projects should be devoted to full access to all the data in the study and takes
responsibility for the integrity of the data and
thyroid nodules, and thyroid cancer (37). specifically study their role in resistance
the accuracy of the data analysis.
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