C LIN I CA L R ES E AR CH A RT IC LE

Thyroid Abnormalities in Patients With Extreme

Insulin Resistance Syndromes

Yevgeniya S. Kushchayeva,1* Sergiy V. Kushchayev,2* Megan Startzell,1

Elaine Cochran,1 Sungyoung Auh,1 Yuhai Dai,3 Marissa Lightbourne,4
Monica Skarulis,1 and Rebecca J. Brown1

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1
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney
Diseases/National Institutes of Health, Bethesda, Maryland 20892; 2Department of Radiology, Johns
Hopkins Hospital, Baltimore, Maryland 21287; 3Clinical Core Laboratory, National Institute of Diabetes and
Digestive and Kidney Diseases/National Institutes of Health, Bethesda, Maryland 20892; and 4National
Institute of Child Health and Human Development/National Institutes of Health, Bethesda, Maryland 20892

ORCiD numbers: 0000-0002-9722-0987 (Y. S. Kushchayeva); 0000-0002-2589-7382 (R. J. Brown).

Context: Insulin and leptin may increase growth and proliferation of thyroid cells, underlying an
association between type 2 diabetes and papillary thyroid cancer (PTC). Patients with extreme
insulin resistance due to lipodystrophy or insulin receptor mutations (INSR) are treated with high-
dose insulin and recombinant leptin (metreleptin), which may increase the risk of thyroid neoplasia.

Objective: The aim of this study was to analyze thyroid structural abnormalities in patients with
lipodystrophy and INSR mutations and to assess whether insulin, IGF-1, and metreleptin therapy
contribute to the thyroid growth and neoplasia in this population.

Design: Thyroid ultrasound characteristics were analyzed in 81 patients with lipodystrophy and 11
with INSR (5 homozygous; 6 heterozygous). Sixty patients were taking metreleptin.

Results: The prevalence of thyroid nodules in children with extreme insulin resistance (5 of 30,
16.7%) was significantly higher than published prevalence for children (64 of 3202; 2%), with no
difference between lipodystrophy and INSR. Body surface area–adjusted thyroid volume was larger
in INSR homozygotes vs heterozygotes or lipodystrophy (10.4 6 5.1, 3.9 6 1.5, and 6.2 6 3.4 cm2,
respectively. Three patients with lipodystrophy and one INSR heterozygote had PTC. There were no
differences in thyroid ultrasound features in patients treated vs not treated with metreleptin.

Conclusion: Children with extreme insulin resistance had a high prevalence of thyroid nodules,
which were not associated with metreleptin treatment. Patients with homozygous INSR mutation
had thyromegaly, which may be a novel phenotypic feature of this disease. Further studies are
needed to determine the etiology of thyroid abnormalities in patients with extreme insulin re-
sistance. (J Clin Endocrinol Metab 104: 2216–2228, 2019)

besity is associated with increased risk of certain
O malignancies, including breast, endometrial, colon,
rectal, and liver cancers (1–4). Both hyperinsulinemia
and hyperleptinemia, which are associated with obesity
and insulin resistance, have been proposed as causal links
between obesity and cancer development (5–8). Al-
though less well studied than other cancers, there is some
evidence to link insulin resistance with thyroid pro-
liferation and differentiated thyroid cancer (9–11). Pa-
tients with skin tags, a marker of hyperinsulinemia,

ISSN Print 0021-972X ISSN Online 1945-7197 *Y.S.K. and S.V.K. contributed equally to this study.
Printed in USA Abbreviations: AUC, area under the curve; BMI, body mass index; BSA, body surface area;
This article is a U.S. Government work-for-hire and is therefore in the public domain in FNA, fine-needle aspiration; IGF-1R, IGF-1 receptor; IR-A, A isoform of the insulin re-
the U.S. ceptor; IR-B, B isoform of the insulin receptor; MEK, mitogen-activated protein kinase;
Received 24 October 2018. Accepted 11 January 2019. OGTT, oral glucose tolerance test; PI3K, phosphatidylinositol 3-kinase; PTC, papillary
First Published Online 16 January 2019 thyroid cancer; US, ultrasound.

2216 https://academic.oup.com/jcem J Clin Endocrinol Metab, June 2019, 104(6):2216–2228 doi: 10.1210/jc.2018-02289
doi: 10.1210/jc.2018-02289
have a higher prevalence of ultrasound (US)-detected
thyroid nodules, size of thyroid nodules, and thyroid
volume (12–14). Furthermore, the insulin sensitizer
metformin reduced thyroid size in patients with type 2
diabetes mellitus (15), supporting the idea that hyper-
insulinemia has a proliferative effect on the thyroid.
Insulin signaling activates two main signaling path-
ways: the insulin receptor substrate/phosphatidylinositol
3-kinase (PI3K) pathway, which is responsible for glu-
cose uptake and most metabolic actions of insulin, and
the Raf/mitogen-activated protein kinase kinase (MEK)/
ERK (MAPK) pathway, which interacts with the PI3K
pathway and controls cell growth and differentiation
(16). Both signaling cascades can be activated by a wide
range of stimuli in addition to insulin, such as leptin and
IGF-1 (17–20). In most forms of insulin resistance, in-
cluding obesity, insulin signaling is impaired in some
intracellular insulin signaling pathways but remains in-
tact in other pathways, referred to as “selective insulin
resistance.” The pathways that are resistant to insulin
vary in a tissue-specific manner (21). In general, it is
thought that insulin signaling via insulin receptor substrate/
PI3K pathways is impaired, whereas Raf/MEK/ERK
signaling remains unaffected.
Syndromes of extreme insulin resistance include
generalized or partial lipodystrophy, in which there is
complete or partial absence of adipose tissue leading to
selective insulin resistance, and insulin receptor mutation
(22, 23) (INSR) syndromes, in which there is a primary
insulin-signaling defect leading to impairment of all in-
sulin signaling pathways, including the Raf/MEK/ERK
pathway (24). Both high-dose insulin and metreleptin are
used as treatments in both conditions (22, 23). There are
no data regarding effects of known mitogenic stimuli
such as hyperinsulinemia and leptin on thyroid pro-
liferation in patients with extreme insulin resistance.
Because a link between milder forms of insulin resistance
and thyroid proliferation has already been shown, we
hypothesized that severe hyperinsulinemia and/or leptin
treatment in patients with extreme insulin resistance
would lead to increased prevalence of proliferative thy-
roid changes. We further hypothesized that patients with
lipodystrophy would have greater prevalence of thyroid
proliferative changes compared with patients with ho-
mozygous or dominant-negative heterozygous INSR
mutations, due to enhanced insulin-mediated stimulation
of the proliferative MAPK pathway in this population.
The aims of this study were to (i) analyze thyroid
structural abnormalities in patients with extreme insulin
resistance due to lipodystrophy or INSR mutation, and
(ii) to assess factors that might contribute to thyroid
growth and neoplasia in these populations, including
insulin, IGF-1, and metreleptin therapy.
https://academic.oup.com/jcem 2217
Material and Methods
Patients
Patients with lipodystrophy or mutations of the insulin receptor
participated in a natural history study of insulin resistance and/or
prospective, open-label interventional studies of metreleptin at
the National Institutes of Health Clinical Center (Bethesda, MD).
Studies were approved by the Institutional Review Board of the
National Institute of Diabetes and Digestive and Kidney Diseases
(NCT00027456, NCT00085982, NCT00005905, NCT00025883,
NCT01778556, NCT02262806, NCT02262832, NCT00001987).
All subjects or their legal guardians provided written in-
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formed consent prior to participation. Minors provided
assent when age appropriate. Eighty-one patients with lip-
odystrophy and 11 patients with INSR mutation had available
thyroid US data.
Thyroid imaging
High-resolution thyroid US was performed using a linear
array 10- to 12-MHz probe. Longitudinal and transverse scans
were performed to measure depth, width, and length of each
lobe. Thyroid lobe volume was calculated as 0.479 3 depth 3
width 3 length (cm). Thyroid volume was calculated as the sum
of the volumes of both lobes, excluding the isthmus. Thyroid
volumes in subjects ,20 years of age were compared with
reference ranges for age and body surface area (BSA) as de-
scribed by Suzuki et al. (25) based on assessment of 34,227
children from an iodine-sufficient area. Thyroid volume in
adults (20 to 70 years of age) were compared with reference
ranges described by Berghout et al. (26) based on analysis of 50
healthy volunteers (25 males and 25 females) from iodine-
sufficient areas (normal ranges within inner limits of the per-
centiles 2.5 and 97.2 are 4.8 6 15.1 mL for women and 7.7 6
19.1 mL for men). Because adults with lipodystrophy and INSR
mutation may have low BSA due to low weight or height, re-
spectively, thyroid volume in adults was also analyzed
according to BSA-based reference ranges described by Suzuki at
al. (25) for healthy volunteers aged 0 to 19 years. Thyroid
volume adjusted for BSA was calculated as total thyroid volume
divided by BSA. BSA was calculated using the formula of Du
Bois and Du Bois (27).
All thyroid ultrasonography studies were reviewed by one
radiologist (S.K.) who was blinded to the patients’ diagnoses.
Thyroid gland appearance on US was characterized based
on echogenicity (homogeneous, heterogeneous), vascularity
(decreased, normal, increased), and presence of cystic lesions
and/or nodules. Nodules were characterized by size, compo-
sition (solid, solid-cystic, spongiform), echogenicity (hypo-
echogenic, isoechogenic, hyperechogenic), shape (taller than
wide, wider than tall), margins (ill-defined, lobulated, smooth),
and presence of calcified foci (peripheral/rim calcifications,
microcalcifications).
Laboratory methods
Laboratory measurements were performed on blood sam-
ples obtained after an 8- to 12-hour fast. All laboratories were
obtained within 1 week of the thyroid US with the exception of
antithyroid antibodies. TSH, free T4, TT4, fT3, TT3, antith-
yroglobulin antibody (ATG2), thyroid peroxidase antibody
(MTPO1), HbA1c, glucose, c-peptide, insulin, and IGF-1 were
measured by the standard techniques of the National Institutes
2218 Kushchayeva et al Thyroid Abnormalities and Extreme Insulin Resistance J Clin Endocrinol Metab, June 2019, 104(6):2216–2228

of Health Clinical Center Laboratory. IGF-2 was measured by a
Quantikine® human IGF-2 immunoassay (R&D Systems,
Minneapolis, MN) in stored serum samples. Sixty-eight samples
were available for analysis (3 INSR2/2, 6 INSR+/2, and 59
lipodystrophy patients). Leptin was determined by radioim-
munoassay (EMD Millipore, formerly Linco Research, St.
Charles, MO). The intraassay and interassay coefficients of
variation were 9.3% and 9.6% respectively. This assay mea-
sures both endogenous leptin and exogenous metreleptin. Prior
studies have shown that most metreleptin-treated patients de-
velop nonneutralizing antibodies that interfere with leptin as-
says, and thus leptin levels measured during metreleptin
Because of age differences between patients with lipodystrophy
vs INSR mutations, comparison between these groups were also
performed in the subgroups of patients aged ,19 years.
Between-group comparisons were performed using a non-
parametric t test, Mann–Whitney test, Wilcoxon matched-pairs
signed rank test, and Fisher’s exact test depending on data type
and distribution. Relationships between duration of metreleptin
treatment in the combined group of lipodystrophy and INSR
mutation patients and thyroid volume, as well as thyroid nodule
size, were determined using Spearman correlation tests. Ana-
lyses were performed using GraphPad Prism version 6
(GraphPad Software, La Jolla, CA). Data are reported as

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treatment may be falsely elevated (28). A 75-g (1.75 g/kg in
patients weighing ,43 kg) oral glucose tolerance test (OGTT)
was performed with measurement of glucose and insulin at
times 210, 0, 30, 60, 90, 120, and 180 minutes relative to the
glucose load. Insulin and glucose area under the curve (AUC)
were calculated using the trapezoidal method.
Statistical methods
The following groups were compared: patients with lip-
odystrophy vs all patients with INSR mutation; patients with
homozygous (INSR2/2) vs heterozygous (INSR+/2) INSR
mutation and vs lipodystrophy; all patients (lipodystrophy and
INSR mutation) treated with metreleptin vs all patients (lip-
odystrophy and INSR mutation) never treated with metreleptin.
mean 6 SD unless otherwise indicated. A P value ,0.05 was
considered statistically significant.
Results
Demographic characteristics
Demographic characteristics of patients, type of INSR
mutation, and phenotypic features are shown in Tables 1
and 2. Among 81 patients with lipodystrophy, 3 had
atypical progeria, 9 had acquired generalized lipodys-
trophy, 27 had congenital generalized lipodystrophy, and
42 had familial partial lipodystrophy. Among 11 patients

Table 1. Characteristics of Patients With INSR Mutation

INSR Mutation, HbA1c Short Dysmorphic Nephrocalcinosis /
Patient Age, y M/F Location Disease (%)a DM AN Stature Featuresb Nephrolithiasis Dyslipidemia
1 20 M Homozygous, RMS 13.3 Y Y Y Y Y N
Ser635Leu
del exons 9
and 10
2 19.2 F Homozygous, RMS 12.9 Y Y Y Y Y N
Ile119Met
3 18.4 M Homozygous, RMS 9.4 Y Y N N Y N
Tyr3X
Glu238Lys
4 12.1 M Homozygous, RMS 10.8 Y Y Y Y Y N
Asn117Lys
del exon 3
5 6.8 F Homozygous, RMS 9.6 Y Y Y Y Y N
Cys293Arg
Gly142Asp
6 22 F Heterozygous, Type A IR 5.1 N Y Y N N N
P1178L
7 47.1 M Heterozygous, Type A IR 4.8 N Y N N N N
Val1029Gly
8 12.1 F Heterozygous, Type A IR 9.2 Y Y N N N N
Pro1178Leu
9 15 F Heterozygous, Type A IR 5.3 N Y N N N N
Pro1236Ala
10 9.3 F Suspected Suspected 5.9 Y Y N N N N
heterozygous type A IR
11 15.4 M Heterozygous, Type A IR 7.2 Y Y N N N N
His1130Arg

Abbreviations: AN, Acanthosis nigricans; DM, diabetes mellitus; F, female; IR, insulin resistance; M, male; N, no; RMS, Rabson– Mendenhall syndrome; Y,
yes.
a
At the time of thyroid US.
b
Dysmorphic features included (but were not limited to) coarse face features, premature aging phenotype, prognathism, macroglossia, dental ab-
normalities such as premature dentition, macrodontia, and crowded/extra teeth.
doi: 10.1210/jc.2018-02289 https://academic.oup.com/jcem 2219

Table 2. Demographics and HbA1c of All Age Patients and >19 y of Age With Extreme Insulin Resistance at
the Time of Thyroid Imaging
All Patients Patients <19 y of Age

INSR Mutation Lipodystrophy INSR Mutation Lipodystrophy

Parameter/Disease (n = 11) (n = 81) P Value (n = 7) (n = 23) P Value
Age, ya 18.1 6 10.6 (7–47) 30.9 6 18 (1–79) 0.01 13.1 6 3.9 (7–18) 13.2 6 4.6 (2–18) 0.81
% Male 45 16 0.036 43 22 0.34
BSA, m2 1.34 6 0.36 1.67 6 0.3 0.006 1.28 6 0.34 1.42 6 0.4 0.33
BMI 21.2 6 4.4 23.3 6 5 0.2 19.3 6 3.2 19.6 6 4.7 0.8
% on Metreleptin 36 67 0.048 29 70 0.08

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HbA1c, % (range) 8.5 6 3.1 (4.8–13.3); 7.1 6 2.1 (4.3–13.2); 0.2 8.2 6 2 (5.3–10.8): 6.42 6 2 (4.3–11); 0.04
n = 11 n = 76 n=7 n = 22

Boldface indicates statistically significant P value (P , 0.05).

a
Age is given as mean 6 SD (range).

with INSR mutation, 5 had homozygous or compound
heterozygous (INSR2/2) and six had heterozygous
(INSR+/2) mutations in the INSR gene. Patients with
INSR mutations were significantly younger than patients
with lipodystrophy (18 6 10 vs 32 6 18 years, P = 0.01)
with higher prevalence of males (45% vs 16%, P = 0.036)
and lower BSA (1.34 6 0.4 vs 1.67 6 0.3 m2, P = 0.006).
There was no difference in body mass index (BMI) be-
tween patients with lipodystrophy vs INSR mutation
(Table 2). When only lipodystrophy and INSR pa-
tients ,19 years old were compared, there were no
differences in sex, BSA, BMI, or metreleptin treatment
(Table 2). Sixty patients were on metreleptin therapy at
the time of thyroid US for a mean of 6.1 6 4.2 years
(range, 0.9 to 16.7 years) for patients with lipodystrophy
and 2.8 6 2.5 years (range, 0.04 to 5.9 years) for patients
with INSR mutation. Thirty-five patients with lipodys-
trophy and five with INSR mutation were on insulin
therapy. Fifty-two patients with lipodystrophy and nine
with INSR mutation were on metformin. Two patients
with lipodystrophy were on pioglitazone in addition to
metformin.
Thyroid function
There were no differences in TSH or thyroid hormone
concentrations in patients with lipodystrophy vs INSR
mutation (Table 3). Among patients with lipodys-
trophy, four were on thyroid hormone replacement for
hypothyroidism and three did not have available thyroid
function tests. Among the remaining 74 patients, four

Table 3. Thyroid Status in Patients With Extreme Insulin Resistance at the Time of Thyroid Imaging
All Patients Patients <19 y of Age

INSR Mutation Lipodystrophy INSR Mutation Lipodystrophy

Parameter/Disease Group Group P Value Group Group P Value
TSH, mIU/mL (range); n 1.78 6 1.38 1.89 6 1.2 0.5 2 6 1.7 2.3 6 1.6 0.6
(0.42–5.1); n = 11 (0.37–6.1); n = 74 (0.42–5.1); n = 7 (0.58–6.08); n = 20
fT4, ng/dL (range); n 1.43 6 0.46 1.22 6 0.2 0.2 1.4 6 0.6 1.27 6 0.17 0.5
(0.8–1.9); n = 4 (0.9–1.8); n = 50 (0.8–1.9); n = 3 (1.1–1.6); n = 14
TT4, mg/dL (range); n 8.73 6 1.7 7.34 6 2.2 0.1 9.2 6 2.3 7.46 6 1.4 0.4
(7–11.7); n = 7 (4.7–15); n = 22 (7.3–11.7); n = 3 (5.3–9.2); n = 5
TT3, ng/dL (range); n 114 6 33 120 6 32.4 0.7 133.8 6 35.4 142.2 6 42 0.9
(71–158.8); n = 6 (75.7–219); n = 25 (108.8–158.8); n = 2 (86.2–219); n = 7
Anti-Thyroglobulin n = 11 n = 80 0.7 n=7 n = 23 0.9
antibodies,a %
Negative 73 80 57.4 61
Detectable 9 6 14.3 13
Unknown 18 14 28.6 26
Anti–thyroid n = 11 n = 80 0.9 n=7 n = 23 0.7
peroxidase
antibodies,a %
Negative 64 61 43 52
Detectable 18 25 29 22
Unknown 18 14 29 26
a
Antithyroid antibodies were checked at any time point, including in patients on replacement therapy.
2220 Kushchayeva et al Thyroid Abnormalities and Extreme Insulin Resistance
(5.4%) had subclinical hypothyroidism defined as ele-
vated TSH with normal thyroid hormone levels; all
others were biochemically euthyroid. Among patients
with INSR mutation, none was taking thyroid hormone.
One patient (9%) had hypothyroidism based on elevated
TSH (5.1 mU/mL) with low T4 (0.8 ng/mL). One patient
(9%) had subclinical hyperthyroidism with low TSH
only. The remaining nine patients (82%) were bio-
chemically euthyroid (Table 3).
Insulin, glycemia, IGF-1, and IGF-2
Patients with INSR2/2 and INSR+/2 mutation had
higher ambient insulin concentrations compared with
lipodystrophy, as evidence by higher fasting insulin and
higher insulin AUC during the OGTT (Table 4). There
was no difference in HbA1c in patients of all ages with
INSR mutation vs lipodystrophy; however, among pa-
tients ,19 years of age, those with INSR mutation had
higher HbA1c compared with those with lipodystrophy
(8.2% 6 2% vs 6.4% 6 2%, P = 0.04). Patients with
INSR2/2 mutation had higher blood glucose concen-
trations compared with both INSR+/2 and lipodystrophy
as evidenced by higher HbA1C (11.2% 6 1.8% vs
6.3% 6 1.7% and 7.1% 6 2.1%, respectively; P =
0.0001); however, fasting glucose and glucose AUC
during the OGTT did not differ between groups
(Table 4). Patients with INSR2/2 mutation had signifi-
cantly lower serum IGF-1 (33.2 6 19 ng/mL) in com-
parison with INSR+/2 mutation (366.3 6 218 ng/mL)
and lipodystrophy (182.8 6 96 ng/mL) (P , 0.0001).
Eighty percent of patients with INSR2/2 had low IGF-1
for age vs 0% in patients with INSR+/2 mutation (P =
0.015) and 16% in lipodystrophy (P = 0.006). Patients
with INSR2/2 (n = 3) had significantly lower IGF-2
(136 6 123 ng/mL) compared with lipodystrophy pa-
tients (449 6 125 ng/mL; n = 59; P = 0.009) but were not
Table 4. Blood Glucose Parameters and IGF-1/IGF-2 Levels in Lipodystrophy and INSR Mutation Patients at
the Time of Thyroid US
2/2
INSR
Fasting insulin, mU/mL 626 6 390
Fasting blood glucose, mg/dL 135 6 75
AUC during OGTT for insulin, 1,103,313 6 18,496 72,758 6 48,780
mU/mL/190 min
AUC during OGTT for blood glucose, 50,966 6 16,478 34,865 6 13,239
mg/dL/190 min
HbA1c, % 11.2 6 1.8
IGF-1, ng/mL 33 6 19
IGF-2, ng/m) 136 6 123
P , 0.05 by post hoc Dunn multiple comparison. Boldface indicates statistically significant P value (P , 0.05).
a
Homozygous INSR mutation vs lipodystrophy group.
b
Homozygous vs heterozygous INSR mutation.
c
Heterozygous INSR mutation vs lipodystrophy group.
J Clin Endocrinol Metab, June 2019, 104(6):2216–2228
statistically different from those with INSR+/2 (347 6
69 ng/mL; n = 6; P = 0.6) (Table 4).
Thyroid imaging
Thyroid volume
There was no difference in thyroid volume in patients
with lipodystrophy vs INSR mutation among patients of
all ages (10.4 6 6.3 and 9.3 6 7.1 mL, respectively; P =
0.3) or those ,19 years of age (8.2 6 8.4 and 6.9 6
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3.7 mL, respectively; P = 0.9) (Table 5). As expected,
thyroid volume correlated with BSA in patients ,19
years of age (r = 0.65, P = 0.0001) but not in those $19
years of age (r = 0.13, P = 0.3). There was no difference in
total thyroid volume corrected for BSA between lip-
odystrophy and INSR mutation among patients of all
ages or those ,19 years of age (Table 4). Among patients
with INSR mutation, thyroid volume corrected for BSA
was significantly larger in patients with INSR2/2 vs
INSR+/2 [10.4 6 5.1 cm2 (range, 4 to 16.6 cm2) vs 3.9 6
1.5 cm2 (range, 1.8 to 6 cm2); P = 0.017; Fig. 1] as well as
INSR2/2 mutation vs lipodystrophy (6.2 6 3.4 cm2;
range, 1.3 to 21.8 cm2; P = 0.046).
Patients with INSR mutation had a 30% frequency of
enlarged thyroid volume for BSA compared with 12% in
those with lipodystrophy, but the difference did not reach
statistical significance (P = 0.07) (Table 5). Among
INSR2/2 patients, three (60%) had enlarged thyroid
volume, one (20%) had thyroid volume at the upper limit
of normal, and only one (20%) was within the normal
range; in contrast, none of the INSR+/2 patients had an
enlarged thyroid gland.
Thyroid structure and vascularity
Echostructure of the thyroid gland was heterogeneous
in 61% and 73% of patients with lipodystrophy and
INSR mutation, respectively (P = 0.5). Most patients had
+/2
INSR Lipodystrophy P Value (ANOVA)
136 6 124 64 6 121 0.0005a
97 6 14 125 6 54 0.5a,b,c
28,596 6 31,238 0.0005a,c
39,873 6 16,930 0.3a,b,c
6.3 6 1.7 7.1 6 2.1 0.003a,b
366 6 218 183 6 96 <0.0001a,b,c
347 6 69 449 6 125 0.0026a
doi: 10.1210/jc.2018-02289 https://academic.oup.com/jcem 2221

Table 5. Thyroid Volume in Patients With Extreme Insulin Resistance at the Time of Thyroid Imaging
All Patients Patients <19 y of Age

INSR Mutation Lipodystrophy INSR Mutation Lipodystrophy

Group (n = 11) Group (n = 70) P Value Group (n = 7) Group (n = 21) P Value
Right lobe, mL (range) 5.1 6 3.5 (1.3–13) 5.8 6 3.4 (1–20.1) 0.3 3.9 6 2.3 (1.3–7.8) 4.4 6 0.8 (1–20.1) 0.9
Left lobe, mL (range) 4.3 6 3.6 (0.9–13.7) 4.6 6 3.3 (0.4–21.15) 0.5 2.9 6 1.5 (0.9–5.1) 3.8 6 4.4 (0.4–21) 0.9
Total volume, mL 9.3 6 7.1 (2.3–26.6) 10.4 6 6.3 (1.5–41.2) 0.3 6.9 6 3.7 (2.3–13) 8.2 6 8.4 (1.5–41.2) 0.9
(range)
Total volume per BSA, 6.8 6 4.8 (1.8–16.6) 6.2 6 3.4 (1.3–22); 0.9 5.7 6 3.8 (1.8–13.6) 5.4 6 4.3 (1.3–22) 0.7
mL/m2 (range) (n = 64)
Not enlarged/enlarged 91/9 83/17 0.7 100/0 81/19 0.3

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thyroid volume
based on age, %a
Not enlarged/enlarged 70/30 (n = 10) 88/12 (n = 51) 0.07 86/14 95/5 (n = 20) 0.3
thyroid volume
based on BSA, %b

Patients were excluded from the analysis when they had history of thyroid surgery, were taking thyroid hormone, or in whom thyroid volume could not be
assessed due to limited US images.
a
Thyroid volumes in subjects ,20 y of age were compared with reference ranges for age (25). Thyroid volume in adults (20 to 70 y of age) were compared
with adult reference ranges (26).
2
Thyroid volumes in both pediatric and adult subjects were compared with reference ranges for BSA derived from children ,20 of age (25).

normal thyroid vascularity with no difference between
lipodystrophy and INSR mutation (96% vs 91%,
P = 0.3).
Thyroid lesions
Cysts. Among patients of all ages, pure cystic lesions (i.e.,
colloid cysts) were present in 60% and 73% of patients
with lipodystrophy and INSR mutation, respectively (P =
0.5). Among patients with colloid cysts, the size of the
largest cyst was 4.3 6 2.6 mm (range, 1 to 8 mm) in
patients with lipodystrophy and 3.3 6 2.7 mm (range, 1
to 17 mm) in patients with INSR mutation (P = 0.2). In
patients ,19 years of age, colloid cysts were present in
36.4% and 71.4% of patients with lipodystrophy and
INSR mutation, respectively (P = 0.2). Among pa-
tients ,19 years of age with cysts, the size of the largest
cyst was 2.7 6 1.2 mm (range, 1 to 4 mm) in patients with
lipodystrophy and 3.4 6 3.1 mm (range, 1 to 8 mm) in
patients with INSR mutation (P = 0.9).
There was no difference in the prevalence of colloid
cysts in patients with extreme insulin resistance (13 of 29,
45%) compared with published prevalence for children
aged 10 to 18 years (1924 of 3202, 60%) (29) (P = 0.1).
Nodules. Thyroid nodule characteristics are shown
in Table 6. Only one 18-year-old patient with INSR

Figure 1. Thyroid ultrasonography in patients with homozygous (2/2) (A) vs heterozygous (+/2) (B) INSR mutations. Patients with INSR2/2
mutations had significantly larger thyroid volume adjusted for BSA (10.4 6 5.1 vs 3.8 6 1.5 mL, P = 0.017). One patient with INSR2/2 mutation
was diagnosed with PTC at age 18 [in (A); thyroid US with white arrow at the location of PTC]. Solid red lines show thyroid gland borders;
dashed red lines indicate that a portion of the thyroid tissue was not captured by the US probe.
2222 Kushchayeva et al Thyroid Abnormalities and Extreme Insulin Resistance J Clin Endocrinol Metab, June 2019, 104(6):2216–2228

mutation had a thyroid nodule; thus, statistical com-
parisons of nodule characteristics in patients with lip-
odystrophy vs INSR mutation were not performed.
In patients ,19 years of age, thyroid nodules were
detected in 4 of 23 (17%) patients with lipodystrophy
and 1 of 7 patients (14%) with INSR mutation. The 0.9-
cm nodule detected in the 18-year-old patient with
INSR2/2 mutation was found to be a papillary thyroid
cancer (PTC) by fine-needle aspiration (FNA) and had
typical US characteristics (very hypoechoic nodule with
31% had macrocalcifications or peripheral calcifications.
There were no nodules with a taller-than-wide shape.
Patients with lipodystrophy and INSR mutations with
no thyroid lesions were significantly younger (16.5 6 6.4
years) in comparison with patients with only colloid cysts
(30.6 6 15.4 years, P = 0.0002) and patients with thyroid
nodules (43.4 6 18.6 years, P , 0.0001). Patients with
colloid cysts but no thyroid nodules were younger than
patients with thyroid nodules (P = 0.0075).

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microcalcifications and ill-defined borders). Diagnosis
was confirmed by pathology evaluation after hemi-
thyroidectomy. In lipodystrophy patients ,19 years of
age, two thyroid nodules were subcentimeter (both
0.4 cm) and two measured 1.0 and 1.2 cm. All nodules
had smooth margins, solid or cystic-solid structure, with
hypoechoic echogenicity in two cases. The 1.2-cm thy-
roid nodule was spongiform with smooth margins,
consistent with low risk for PTC. The prevalence of
thyroid nodules in patients with extreme insulin re-
sistance aged ,19 years (5 of 30, 16.7%) was signifi-
cantly higher than the published prevalence for children
aged 10 to 18 years (64 of 3202, 2%) (29) (P = 0.0004).
In patients of all ages, thyroid nodules were detected in
29 of 80 (36.3%) patients with lipodystrophy. These 29
patients had 55 nodules with size 0.9 6 0.4 cm (range,
0.3 to 2.7). US features of these nodules are described in
Table 6. Most nodules had smooth margins (74.5%).
None had extrathyroidal extension. Sixty percent of
nodules were hypoechoic, 73% had calcifications, and
Cytopathology/histopathology diagnoses of
thyroid nodules
Among 55 nodules in the lipodystrophy group, 48
(87%) lesions did not meet the criteria for FNA owing to
small size or benign characteristics based on American
Thyroid Association recommendations (30). Seven
nodules in six patients had indications for FNA. PTC was
proved by histopathology in four nodules in three pa-
tients; one was an adenomatoid nodule, and two showed
atypia of unknown significance. The one thyroid nodule
in a patient with INSR mutation was shown to be PTC by
FNA and histology, as described above.
Effect of metreleptin on thyroid structure
and function
Thyroid structural changes in patients treated and
not treated with metreleptin
In the combined group with lipodystrophy or INSR
mutation, 60 patients were treated and 32 were never treated
with metreleptin. There were no differences in age, BSA,

Table 6. Thyroid Nodule Description in Lipodystrophy and INSR Mutation Groups

All Patients Patients <19 y of Age

Parameters INSR Mutation Lipodystrophy INSR Mutation Lipodystrophy

N 11 80 7 23
Patients with nodules, n (%) 1 (9.1%) 29 (36.3%) 1 (14.3%) 4 (17.4%)
Number of nodules 1 55 1/1 4/4
Size, cm 0.9 0.86 6 0.42 (0.3–2.7) 0.9 1.2; 1; 0.4; 0.4
Composition
Solid 1 22 1 2
Solid–cystic/spongiform 0 33 0 2
Echogenicity
Hyperechoic 0 6 0 1
Hypoechoic 0 33 0 3
Very hypoechoic 1 12 1 0
Isoechoic 0 4 0 0
Margins
Smooth 0 41 0 4
Ill-defined 1 12 1 0
Lobulated/irregular 0 2 0 0
Extrathyroidal extension 0 0 0 0
Foci (calcifications)
None 0 15 0 4
Microcalcifications 1 40 1 0
Macrocalcifications 0 2 0 0
Rim/peripheral 0 15 0 0
doi: 10.1210/jc.2018-02289
absolute or BSA-adjusted thyroid volume, echogenicity,
or prevalence of nodules/cysts/calcifications in the treated
vs untreated patients (Table 7). In the subgroup with lip-
odystrophy, there were no differences in these parameters in
the treated (n = 25) vs not treated (n = 56) patients.
Three patients with lipodystrophy and one with INSR
mutation were diagnosed with PTC at the age of 18.4, 24,
and 40 years, and one of them was never treated with
metreleptin (age at the time of PTC diagnosis was 18.8 years).
In the subgroup with INSR mutation, there was no
difference in age and BSA between metreleptin-treated
and untreated patients. Of note, all four metreleptin-
treated patients had INSR2/2 mutation, whereas only
one of seven nontreated patients had INSR2/2 mutation.
Thyroid volume was higher in the metreleptin-treated vs
the nontreated group (15.4 6 8.6 vs 5.9 6 2.7 mL, re-
spectively; P = 0.04). BSA adjusted thyroid volume was
also higher in the treated vs untreated group (11.4 6 5.4
vs 4.3 6 1.7 mL, P = 0.042). All four metreleptin-treated
patients with INSR mutation had cystic thyroid lesions,
vs four of seven patients in the untreated group (P = 0.2).
The only thyroid nodule in the INSR mutation group was
found in patients with INSR2/2 mutation.
In all patients with extreme insulin resistance (lip-
odystrophy plus INSR mutation), there was no signifi-
cant association between the duration of metreleptin
treatment and thyroid volume (P = 0.2, r = 0.7) as well as
BSA-adjusted thyroid volume (P = 0.8, r = 0.04). Du-
ration of treatment did not correlate with the size of
thyroid nodules in a combined group (lipodystrophy and
INSR mutation patients) (P = 0.2, r = 20.30).
Thyroid function in patients treated and not treated
with metreleptin
In the combined group with lipodystrophy or INSR
mutation, there was no statistical difference in TSH,
Table 7. Thyroid Structural Features in Lipodystrophy and INSR Mutation Groups Based on Leptin Treatment
Never on Leptin (n = 32)
Age, y 32 6 18.5 (7–66)
BSA, m2 1.65 6 0.3 (0.77–2.12)
Thyroid volume, mL 9.4 6 6 (2.3–28.2)
Echogenicity
Homogeneous, n, % 12, 37.5
Heterogeneous, n, % 20, 62.5
Cysts
Yes, n, % 18, 56
No, n, % 14, 44
Nodules
Yes, n, % 7, 22
No, n, % 25, 78
Number of nodules/patients 11/7
Peripheral/rim calcifications, n, % 2, 18.2
a
One patient each in the INSR mutation and lipodystrophy groups were previously treated with leptin (duration of 1 to 4.3 y) but not taking leptin at the
time of US.
https://academic.oup.com/jcem 2223
thyroid hormone levels, or prevalence of patients with
detectable antithyroid antibodies (antithyroglobulin or
anti–thyroid peroxidase) between metreleptin-treated vs
non–metreleptin-treated patients (Table 8). Similarly, in
the subgroup with lipodystrophy, there were no differ-
ences in these parameters between metreleptin-treated vs
untreated patients. In the subgroup with INSR mutation,
there were no differences in thyroid parameters.
Discussion
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In this study, we hypothesized that enhanced insulin
signaling through the mitogenic MAPK pathway would
lead to increased thyroid growth and neoplasia in pa-
tients with selective insulin resistance due to lipodys-
trophy compared with those with nonselective insulin
resistance (including MAPK pathways) in INSR muta-
tion. Counter to our hypothesis, we found that only
patients with INSR2/2 mutation had elevated thyroid
volume in comparison with patients with INSR+/2 mu-
tation, lipodystrophy, and healthy controls (25, 26). We
further hypothesized that metreleptin treatment might
contribute to thyroid proliferation (again through MAPK
signaling), but counter to our hypothesis we did not
observe an association between metreleptin treatment
and thyroid size or nodularity.
In the general population, insulin resistance has been
associated with increased thyroid volume and increased
risk of benign and malignant thyroid lesions (10, 11, 31,
32), whereas treatment with the insulin sensitizer met-
formin has the opposite effects, including an anti-
mitogenic effect on differentiated human thyroid cells
and thyroid cancer cells (33), as well as reduced thyroid
volume in patients with type 2 diabetes (15). The biology
underlying these associations between insulin resistance
and thyroid proliferation has not been fully elucidated.
On Leptina (n = 60) P Value
30 6 18 (2–80) 0.9
1.62 6 0.35 (0.47–2.19) 0.7
11 6 6.8 (1.5–41.2) 0.2
0.3
37, 62
23, 38
0.5
38, 63
22, 38
0.1
23, 38
37, 62
45/23
11, 24.4 0.9
2224 Kushchayeva et al Thyroid Abnormalities and Extreme Insulin Resistance
Table 8. Thyroid Function Tests and HbA1c in Lipodystrophy and INSR Mutation Groups Based on
Metreleptin Treatment
Never on Leptin (n = 32)
TSH, mIU/mL (range); n
fT4, ng/dL (range); n
TT4, mg/dL (range); n
TT3, ng/dL (range); n
Positive antithyroid antibodies,a %; n
HbA1c, % (range
a
Antithyroid antibodies were checked at any time point.
Although thyroid tissue is not a classical insulin sensitive
tissue such as liver, fat, or muscle (34), insulin receptors
are expressed in thyrocytes (31, 35). Insulin resistance
leads to hyperinsulinemia, which leads to increased
stimulation of insulin receptors. In most forms of insulin
resistance, including obesity and type 2 diabetes, insu-
lin stimulation of the MAPK signaling pathway via
insulin receptors is preserved. Hence, hyperinsulinemia is
thought to overstimulate MAPK pathways, leading to
mitogenic effects. Furthermore, hyperinsulinemia can
stimulate the IGF-1 receptor (IGF-1R), again resulting in
overstimulation of MAPK pathways and mitogenic ef-
fects (36–39). These mitogenic effects of insulin via both
the insulin receptor and IGF-1R are independent of TSH
(40, 41). Additionally, insulin is permissive for the mi-
togenic actions of TSH in human thyroid cells in primary
culture (40), and crosstalk between the TSH receptor
and IGF-1R in regulation of thyroid function in human
thyrocytes in vitro was demonstrated (42).
Thus, we had hypothesized that patients with INSR
mutations would demonstrate less mitogenic effects of
hyperinsulinemia vs those with lipodystrophy, as INSR
mutation leads to a blockade of insulin signaling in the
mitogenic MAPK pathway. Counter to our hypothesis,
we observed significantly larger thyroid volume adjusted
for BSA compared with patients with heterozygous INSR
mutations and lipodystrophy, and most patients with
homozygous INSR mutation had enlarged thyroid vol-
ume in comparison with published thyroid volume ref-
erence ranges in patients 0 to ,19 years of age adjusted
for BSA from an iodine-sufficient area (25).
A possible explanation for our finding is that in-
creased thyroid proliferation in INSR2/2 mutations
may be mediated by hyperinsulinemia acting through
IGF-1R. IGF-1 is a more potent stimulus for activation
of MAPK pathways than insulin (18), and proliferative
effects of insulin are at least partially mediated via IGF-
1R. Knockout of the insulin receptor in different tissues,
J Clin Endocrinol Metab, June 2019, 104(6):2216–2228
On Leptin (n = 60) P Value
1.8 6 1 (0.58–5.05); 1.9 6 1.3 (0.37–6.08); 0.8
n = 28 n = 57
1.2 6 0.4 (0.8–1.9); 1.2 6 0.2 (0.9–1.7); 0.3
n=8 n = 46
7.5 6 2.3 (4.7–15); 8 6 1.9 (5.3–11.7); 0.1
n = 17 n = 12
112 6 27 (71–164); 127 6 37 (93–219); 0.2
n = 19 n = 12
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23; n = 22 36; n = 50 0.9
6.7 6 1.8 (4.4–11); 7.5 6 2.5 (4.3–13.3); 0.2
n = 28 n = 59
including the thyroid gland, led to overexpression of
IGF-1R (35, 43). It has been also shown that insulin and
IGF-1 acting through IGF-1R induce protein synthesis
and cell hypertrophy in human thyroid cells (44). Thus,
IGF-1R signaling might be involved in the development
of thyroid morphological abnormalities. This may be
particularly relevant in the presence of impaired INSR
signaling, as increased activation of IGF-1R has been
demonstrated in cultured skeletal muscle from mice
with knockout of the insulin receptor in bone and
thyroid tissue (35, 43, 45).
The larger thyroid size in INSR2/2 patients was not
secondary to direct mitogenic effects of IGF-1, as this
group had markedly low serum IGF-1 levels. Insulin
levels in patients with INSR 2/2 mutations were 10-fold
above the IC50 of insulin at the IGF-1R, suggesting that
insulin action at the IGF-1R could have stimulated
thyroid growth (46). Additionally, low IGF-1 might
upregulate expression of IGF-1R in patients with
INSR2/2 mutations, as has been demonstrated in vitro
and in vivo. For comparison, insulin levels in patients
with INSR+/2 and lipodystrophy were approximately
onefold to twofold the IC50 of insulin at the IGF-1R,
making stimulation of IGF-1R by insulin less relevant
as a mechanism for thyroid growth and proliferation.
Circulating and locally produced IGF-2 could also
contribute to development of thyroid nodules and/or
thyromegaly because both IGF-1 and IGF-2 are in-
volved in cell proliferation and have high homology to
each other and to insulin. Moreover, in insulin resis-
tance, hyperinsulinemia can inhibit hepatic production
of IGFBP-1 and IGFBP-2, leading to increased bio-
availability of IGF-1 and IGF-2 (47). Unfortunately, free
IGF-1 and IGF-2 levels were not available in this study.
Analysis of IGF-2 in our cohorts showed low IGF-2 in
patients with INSR2/2, suggesting that this is unlikely
play a major role in thyroid proliferation in these
patients.
doi: 10.1210/jc.2018-02289 https://academic.oup.com/jcem 2225

Paracrine actions of IGF-1 and IGF-2 might also
stimulate thyroid proliferation by binding to the A iso-
form of the insulin receptor (IR-A). IR-A is the major
mediator of mitogenic effects of insulin, whereas the B
isoform (IR-B) is the major mediator of metabolic effects
of insulin (48). Relative expression of IR-A vs IR-B in
humans or animals with INSR mutations has not been
studied. However, in INSR mutations, both IR-A and IR-
B isoforms would be expected to have reduced binding
affinity for ligands or reduced signal transduction.
differ from published data and is thus unlikely to
represent a pathologic finding (29, 52). Among patients
of all ages, thyroid nodules were more prevalent (36%) in
patients with lipodystrophy compared with those with
INSR mutation (9%); however, this can be explained by
significant demographic differences (age, sex) between
groups. Interestingly, patients ,19 years old with ex-
treme insulin resistance had a high prevalence of thyroid
nodules (17% and 14% for lipodystrophy and INSR
mutation) in comparison with a published prevalence of

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Another mechanism that could theoretically play a
role in the thyroid enlargement in INSR2/2 mutation
patients is stimulation of hybrid receptors formed by an
INSR ab-hemireceptor and an IGF-1R ab-hemireceptor.
Formation of hybrid receptors is stimulated by hyper-
insulinemia (49, 50), and hence they are likely to be more
abundant in INSR2/2 patients. Because the hybrid re-
ceptors behave as IGF-1R rather than insulin receptors,
their stimulation by insulin may contribute to thyroid
growth (49, 51). However, it is unclear how functional
hybrid receptors are in patients with INSR 2/2 mutation.
Thus, the combination of severe hyperinsulinemia with
low IGF-1/IGF-2 may lead to thyroid growth in pa-
tients with INSR 2/2 by insulin binding to IGF-1R, by
upregulation of IGF-1R expression, and by insulin binding
to hybrid receptors (Fig. 2; Table 9).
Patients with extreme insulin resistance had high de-
tection rates of colloid cysts; however, this rate did not
;2% in children (29, 52). However, the size of our
cohort is small, and these findings require verification in
larger populations. All nodules in our pediatric cohort
of extreme insulin resistance were diagnosed after age
9 years, and two patients had PTC diagnosed at age 18.4
and 18.8 years. Thus, thyroid US starting at a pubertal
age might be considered for early detection of thyroid
abnormalities in patients with extreme insulin resistance.
We are currently conducting longitudinal follow-up in
this cohort to better understand the risk of malignancy.
An unexpected finding was that 26.8% of nodules had
rim/peripheral calcifications. This prevalence of rim
calcification is substantially higher than the 1.78% re-
ported in 2123 surgically removed thyroid nodules in
1498 patients (53). The pathogenesis of calcification in
benign thyroid lesions is thought to begin with hyper-
plasia of fibrous thyroid tissue that affects follicular
blood supply, resulting in hemorrhage and necrosis,

Figure 2. Proposed mechanism of thyroid enlargement in patients with homozygous INSR mutation. Solid blue arrows indicate intact signaling
pathways. Dashed black arrows indicate inhibited signaling pathways. Red Xs indicate blocked receptors and downstream signaling. In patients
with homozygous INSR mutation the proliferative effect on thyroid tissue might be mediated via the direct stimulation of IGF-1R by a high
concentration of circulating insulin and/or hyperinsulinemia-mediated upregulation of hybrid receptors (+). A low level of IGF-1 can upregulate
the number of IGFR1 receptors (++) and/or increase IGF-1R activity, resulting in increased insulin binding to IGF-1Rs with further stimulation of
the MAPK pathway. MAPK-mediated proliferative signaling will lead to thyroid enlargement.
2226 Kushchayeva et al Thyroid Abnormalities and Extreme Insulin Resistance
Table 9. Thyroid Phenotypes and Growth Factors in Patients With Extreme Insulin Resistance
INSR, Homozygous
Insulin resistance Nonselective
IGF-1 ↓ Normal
Fasting insulin ↑↑↑
Thyroid functional status Euthyroid
Thyroid size Enlarged
Risk for thyroid nodules Probably increased
Risk of thyroid cancer Unknown
resulting in calcification of the cyst wall (53). We spec-
ulate that in states of extreme insulin resistance, high
endogenous insulin may stimulate growth of susceptible
thyroid follicular cells, leading to rapid thyroid nodule
enlargement causing ischemia and calcification.
We hypothesized that metreleptin therapy could con-
tribute to thyroid growth and neoplasia. Although leptin
and insulin receptors are not related, leptin signal trans-
duction does act through some components of the insulin
signaling cascade, including PI3K and MAPK pathways
(19). To date, there is no direct evidence of a role of leptin
in the development of thyroid cancer; however, patients
with differentiated thyroid cancer have been reported to
have BMI-independent elevation in leptin level (54). In this
study, we did not observe any increase in thyroid nodules
with metreleptin treatment, despite relatively long dura-
tion of metreleptin therapy (up to 16.7 years in lipodys-
trophy patients and 6 years in patients with INSR
mutation). In patients with lipodystrophy, metreleptin
reduces insulin resistance and hyperinsulinemia, hence the
theoretical growth-promoting effects of metreleptin might
be counteracted by the reduced effects of insulin. How-
ever, metreleptin is not expected to reduce insulin re-
sistance in patients with INSR mutation, hence any effects
of metreleptin to promote thyroid growth and neoplasia
might be better observed in this cohort. We did observe
that metreleptin-treated patients with INSR mutation, but
not metreleptin-treated patients with lipodystrophy, had
higher BSA-adjusted thyroid size vs untreated patients.
Because this difference was only observed in the INSR
mutation cohort, it likely relates to the fact that all
metreleptin-treated INSR patients had homozygous mu-
tations, rather being secondary to metreleptin treatment.
Based on our observations, patients with extreme
insulin resistance have different thyroid phenotypes
based on underlying genetic abnormalities, and thyro-
megaly might be a new phenotypical feature of extreme
insulin resistance due to homozygous INSR mutation
(Fig. 2; Table 8).
In conclusion, we found that patients with extreme
insulin resistance have a high prevalence of thyroid
nodules, metreleptin treatment was not associated with
changes in thyroid size or nodularity, and patients with
J Clin Endocrinol Metab, June 2019, 104(6):2216–2228
INSR, Heterozygous Lipodystrophy
Nonselective Selective
Normal
↑↑ ↑
Euthyroid Euthyroid
Normal Normal
Probably increased Probably increased
Unknown Unknown
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homozygous INSR mutation have significantly enlarged
thyroid glands, which may be a novel phenotypic feature
of this disease. We proposed the possible explanation for
thyroid abnormalities in each group based on our find-
ings (Figs. 1 and 2). Strengths of this study include
analysis of a large cohort of rare patients with lipodys-
trophy and INSR mutations, with and without metre-
leptin treatment. Limitations include small sample size
for patients with INSR mutation, comparison of thyroid
volume and nodularity to published controls, rather than
an internal control group, as well as a young patient
population (especially among patients with INSR mu-
tation). Prospective, longitudinal studies are needed to
clarify the effects of extreme insulin resistance and/or
metreleptin treatment on nodules/cancer development,
and mechanistic studies are needed to determine the
etiology of thyroid abnormalities in patients with ex-
treme insulin resistance.
Acknowledgments
We thank Dr. Mary Walter and members of the National In-
stitutes of Health Clinical Core Laboratory for support in per-
forming assays.
Financial Support: This work was supported by the
Intramural Research Program of the Diabetes, Endocrinology,
and Obesity Branch of the National Institute of Diabetes and
Digestive and Kidney Diseases.
Correspondence and Reprint Requests: Rebecca J. Brown,
MD, National Institutes of Health, Building 10, Room 6-5940,
10 Center Drive, Bethesda, Maryland 20892. E-mail:
brownrebecca@niddk.nih.gov.
Disclosure Summary: The authors have nothing to
disclose.
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