Download Detection of 3-Iodothyronamine in Human Patients: A Preliminary

J C E M
B r i e f
R e p o r t — E n d o c r i n e
O N L I N E
R e s e a r c h
Detection of 3-Iodothyronamine in Human Patients:
A Preliminary Study
Elena Galli,* Maja Marchini,* Alessandro Saba, Sergio Berti,
Massimo Tonacchera, Paolo Vitti, Thomas S. Scanlan, Giorgio Iervasi,
and Riccardo Zucchi
Scuola Superiore S. Anna (E.G.), 56127 Pisa, Italy; Dipartimento di Scienze dell’Uomo e dell’Ambiente
(M.M., A.S., R.Z.) and Dipartimento di Endocrinologia (M.T., P.V.), University of Pisa, 56126 Pisa, Italy;
Fondazione Gabriele Monasterio (S.B.), Ospedale del Cuore, 54100 Massa, Italy; Departments of
Physiology and Pharmacology and Cell and Developmental Biology (T.S.S.), Oregon Health and Science
University, Portland, Oregon 97239; and Istituto di Fisiologia Clinica (G.I.), 56124 Pisa, Italy
Context and Objective: The primary purpose of this study was to detect and quantify 3-iodothyronamine (T1AM), an endogenous biogenic amine related to thyroid hormone, in human blood.
Design: T1AM, total T3, and total T4 were assayed in serum by a novel HPLC tandem mass spectrometry assay, which has already been validated in animal investigations, and the results were
related to standard clinical and laboratory variables.
Setting and Patients: The series included one healthy volunteer, 24 patients admitted to a cardiological ward, and 17 ambulatory patients suspected of thyroid disease, who underwent blood
sampling at admission for routine diagnostic purposes. Seven patients were affected by type 2
diabetes, and six patients showed echocardiographic evidence of impaired left ventricular
function.
Interventions: No intervention or any patient selection was performed.
Main Outcome Measures: serum T1AM, total and free T3 and T4, routine chemistry, routine hematology, and echocardiographic parameters were measured.
Results: T1AM was detected in all samples, and its concentration averaged 0.219 ⫾ 0.012 pmol/ml.
The T1AM concentration was significantly correlated to total T4 (r ⫽ 0.654, P ⬍ 0.001), total T3 (r ⫽
0.705, P ⬍ 0.001), glycated hemoglobin (r ⫽ 0.508, P ⫽ 0.013), brain natriuretic peptide (r ⫽ 0.543,
P ⫽ 0.016), and ␥-glutamyl transpeptidase (r ⫽ 0.675, P ⬍ 0.001). In diabetic vs. nondiabetic patients
T1AM concentration was significantly increased (0.232 ⫾ 0.014 vs. 0.203 ⫾ 0.006 pmol/ml, P ⫽
0.044), whereas no significant difference was observed in patients with cardiac dysfunction.
Conclusions: T1AM is an endogenous messenger that can be assayed in human blood. Our results
are consistent with the hypothesis that circulating T1AM is produced from thyroid hormones and
encourage further investigations on the potential role of T1AM in insulin resistance and heart
failure. (J Clin Endocrinol Metab 97: E69 –E74, 2012)
-Iodothyronamine (T1AM) is a decarboxylated and
partially deiodinated derivative of thyroid hormone,
which can interact with different molecular targets, namely
(1– 8) trace amine associated receptor 1, and possibly other
3
members of the same family of G protein-coupled receptors;
several monoamine transporters and organic anion transporters, including thyroid hormone transporters; mitochondrial F0F1-ATP synthase. Exogenous T1AM has been re-
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/jc.2011-1115 Received March 29, 2011. Accepted September 28, 2011.
First Published Online October 25, 2011
* E.G. and M.M. contributed equally to this work.
Abbreviations: BNP, Brain natriuretic peptide; FT3, free T3; FT4, free T4; ␥GT, ␥-glutamyl
transpeptidase; HbA1c, glycated hemoglobin; HPLC-MS/MS, HPLC coupled to tandem
mass spectrometry; T1AM, 3-iodothyronamine.
J Clin Endocrinol Metab, January 2012, 97(1):E69 –E74
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Galli et al.
T1AM in Human Blood
ported to produce a wide array of functional effects in
isolated organs and whole animals, such as reduced body
temperature (1), reduced heart rate and contractility (1, 9,
10), reduced glucose and increased lipid metabolism (11),
decreased insulin and increased glucagon secretion (12, 13),
and either increased (14) or decreased (15) food intake.
T1AM has been detected in animal tissues by semiquantitative techniques (1, 9, 11), but the presence of T1AM in
human blood has been disputed because after a few preliminary reports that were presented at scientific meetings
(8, 16), negative results have been published (17). This is
a crucial issue because detecting T1AM in human blood
would be consistent with a role as a chemical messenger
and provide the basis to investigate its role in human physiology and pathophysiology. We have recently developed
a novel technique, based on HPLC coupled to tandem
mass spectrometry (HPLC-MS/MS), which allowed quantitative assay of T1AM in rat blood and tissues (18). In the
present investigation this method was used in a small series
of human blood samples. The primary aim was to prove
that T1AM is an endogenous compound in humans. In
addition, we evaluated the relationship between T1AM
concentration, thyroid hormone concentration, and some
common clinical chemistry variables.
Materials and Methods
This investigation involved two groups of patients. The first
group (group A) consisted of 24 consecutive patients admitted to
the Cardiological Division of Massa Hospital (Massa, Italy).
Because the results obtained in this group suggested a correlation
between T1AM and thyroid hormone concentration, we also
investigated 17 patients affected by or suspected of thyroid disease who were followed up by the cardiovascular risk unit of the
Institute of Clinical Physiology in Pisa (group B). Blood samples
were taken at admission, and HPLC-MS/MS assays were performed whenever a sufficient amount of blood was available
after performing the routine laboratory examinations that were
prescribed for diagnostic purposes. Free T3 (FT3) and free T4
(FT4) were determined by the Architect chemiluminescent microparticle immunoassay (Abbott Diagnostics, Abbott Park, IL).
The final diagnosis was established on the basis of echocardiography, coronary arteriography, or peripheral angiography, as
required. All patients gave informed consent to the present investigations, which was approved by the institutional ethical
committee. A healthy volunteer (one of the authors of this paper)
was also included in the study.
Serum samples were collected (1 ml), placed in a 15 ml Teflon
centrifuge tube and spiked with appropriate internal standards,
i.e. 6 pmol D4-T1AM, 50 pmol 13C6-T4, or 50 pmol of 13C6-T3.
Sample processing and an HPLC-MS/MS assay were performed
as described previously (18). The T1AM assay was characterized
by a limit of detection around 12.5 pg/ml (35 fmol/ml). Good
linearity was observed within 3.5 orders of magnitude (r ⫽
0.996), whereas intra- and interassay coefficients of variation
were 7% or less and 12% or less, respectively (the lowest T1AM
J Clin Endocrinol Metab, January 2012, 97(1):E69 –E74
concentration tested was 0.05 pmol/ml). The assays were performed on different days, and to reduce variability, serum samples from the healthy volunteer were included in each set and
used as a calibration reference.
Results are expressed as mean ⫾ S⌭⌴. Differences between
groups were evaluated by unpaired t test. Correlations between
variables were evaluated by linear regression analysis. The
threshold of statistical significance was set at P ⫽ 0.05. GraphPad Prism version 4.1 for Windows (GraphPad Software, San
Diego, CA) was used for data processing and statistical
analysis.
Results
Our series included 20 males and 22 females, with an
average age of 58.1 ⫾ 1.6 yr. In group A the reason for
admission was chest pain in 12 patients, dyspnea in seven
patients, intermittent claudication in two patients, repetitive transient ischemic attacks in one patient, syncope in
one patient, and control of abdominal aortic aneurism in
one patient. The final diagnosis was coronary artery disease in six patients, valvular heart disease in three patients,
dilated cardiomyopathy in two patients, chronic atrial fibrillation in one patient, internal carotid artery stenosis in
two patients, peripheral vascular disease with lower limb
ischemia in two patients, and abdominal aortic aneurism
in one patient. Seven patients admitted for chest pain were
found to be free from significant coronary artery disease.
Group B included four patients affected by untreated hypothyroidism due to autoimmune thyroiditis, three patients affected by untreated hyperthyroidism (Graves’ disease or multinodular toxic goiter), three athyreotic
patients treated with exogenous levothyroxine yielding
normal FT3 and FT4, and seven patients with normal thyroid function. Two group A patients were chronically taking oral L-thyroxine at suppressive dosage because of
multinodular goiter. Most patients received additional
chronic pharmacological treatment (see Table 1), which
was not discontinued due to ethical reasons.
The average values for routine laboratory examinations and echocardiographic variables are summarized in
Table 1. Representative HPLC-MS/MS tracings are
shown in Fig. 1 (panel A), and the overall results are included in Table 1. T1AM was detected in all patients and
its serum concentration averaged 0.219 ⫾ 0.012 pmol/ml,
whereas serum T3 and T4 concentrations averaged 1.52 ⫾
0.11 and 142.32 ⫾ 16.20 pmol/ml, respectively. The ratio
of FT3 to T3 was on the order of 0.2%, whereas the ratio
of FT4 to T4 was on the order of 0.01%. These ratios are
similar to the ratio of free vs. total hormone content as
estimated by conventional techniques (18).
To investigate the determinants of T1AM concentration, we analyzed its correlation with different clinical and
J Clin Endocrinol Metab, January 2012, 97(1):E69 –E74
TABLE 1.
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Clinical and laboratory variables
Variable
T1AM (pmol/ml)
T3 (pmol/ml)
T4 (pmol/ml)
FT3 (fmol/ml)
FT4 (fmol/ml)
TSH (␮IU/ml)
Age (yr)
Weight (kg)
Height (cm)
BMI (kg/m2)
BSA (m2)
Hb (g/dl)
Hct (%)
Glucose (mg/dl)
HbA1c (%)
Creatinine (mg/dl)
Urea (mg/dl)
Uricemia (mg/dl)
Albumin (g/dl)
Proteins (g/dl)
BNP (ng/ml)
AST (IU/ml)
ALT (IU/ml)
␥GT (IU/ml)
ALP (IU/ml)
CK (IU/ml)
Fibrinogen (mg/dl)
Cholesterol (mg/dl)
HDL cholesterol (mg/dl)
LDL cholesterol (mg/dl)
Triglycerides (mg/dl)
Heart rate (beats/min)
Systolic AP (mm Hg)
Diastolic AP (mm Hg)
Left ventricle EDV (ml)
Left ventricle EF (%)
Left ventricle mass (g)
Mean ⴞ SEM
0.219 ⫾ 0.012
1.52 ⫾ 0.11
142.32 ⫾ 16.20
3.18 ⫾ 0.26
13.46 ⫾ 0.96
6.65 ⫾ 2.88
58 ⫾ 2
78 ⫾ 4
169 ⫾ 2
27.4 ⫾ 1.3
1.89 ⫾ 0.04
13.1 ⫾ 0.4
38.9 ⫾ 1.7
119 ⫾ 7
6.0 ⫾ 0.2
1.00 ⫾ 0.06
44.1 ⫾ 4.1
5.2 ⫾ 0.3
3.7 ⫾ 0.1
6.7 ⫾ 0.1
122 ⫾ 26
18 ⫾ 1
16 ⫾ 2
31 ⫾ 5
67 ⫾ 5
104 ⫾ 12
297 ⫾ 14
175 ⫾ 6
54 ⫾ 2
101 ⫾ 6
97 ⫾ 6
70 ⫾ 3
129 ⫾ 4
75 ⫾ 2
127 ⫾ 9
54 ⫾ 2
225 ⫾ 11
Correlation coefficient
vs. T1AM
1
0.705
0.654
0.550
0.339
⫺0.049
0.013
0.152
0.183
0.050
0.172
0.216
0.270
0.198
0.508
⫺0.079
⫺0.029
0.023
0.020
⫺0.135
0.543
0.138
0.008
0.675
0.121
0.194
0.337
⫺0.186
⫺0.039
⫺0.227
0.172
0.173
⫺0.148
⫺0.249
0.051
⫺0.082
0.084
P value
⬍0.001
⬍0.001
⬍0.001
0.037
NS
NS
NS
NS
NS
NS
NS
NS
NS
0.013
NS
NS
NS
NS
NS
0.016
NS
NS
⬍0.001
NS
NS
0.115
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
Data represent mean ⫾ SEM of 42 patients (group A ⫹ group B) with regard to T1AM, T3, T4, FT3, FT4, TSH, and age and 25 patients (group A) for
the other variables. In some patients a few variables were not available: there were 10 missing values for left ventricle EDV, six missing values for
BNP, five missing values for left ventricle mass, and three or fewer missing values in all other cases. Values of P ⱖ 0.200 are not shown. See text
for correlations in specific subgroups. Several patients were receiving chronic pharmacological treatment. Assumed drugs included furosemide,
thiazide diuretics, nitrates, etezimibe, proton pump inhibitors, digoxin, cetirizime, allopurinol, aliskiren, monoxidine, trimetazidine, low-molecularweight heparin, sulfonylureas, and metformin. Five patients were assuming levothyroxine, as detailed in Results. BMI, Body mass index; BSA, body
surface area, Hb, hemoglobin; Hct, hematocrit; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alcaline phosphatase; CK,
creatine kinase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; AP, aortic pressure; EDV, end diastolic volume; EF, ejection fraction;
NS, not significant.
biochemical variables. The results are included in Table 1,
whereas selected scatter plots are shown in Fig. 1 (panels
B–E). T1AM concentration was significantly related to T4
(r ⫽ 0.654, P ⬍ 0.001), T3 (r ⫽ 0.705, P ⬍ 0.001), FT4 (r ⫽
0.339, P ⫽ 0.037), and FT3 (r ⫽ 0.550, P ⬍ 0.001). A
significant correlation with T4 was observed even if analysis was limited to group A patients (r ⫽ 0.450, P ⫽
0.024). Significant correlations were also observed
between T1AM and glycated hemoglobin (HbA1c; r ⫽
0.508, P ⫽ 0.013), brain natriuretic peptide (BNP; r ⫽
0.543, P ⫽ 0.016), or ␥-glutamyl transpeptidase (␥GT;
r ⫽ 0.675, P ⬍ 0.001).
Because HbA1c is widely used as an index of persistent
hyperglycemia, we investigated whether diabetes may be
associated with differences in T1AM levels. In group A, a
full screening for diabetes was performed, and seven patients were diagnosed as affected by type 2 diabetes on the
basis of standard clinical criteria, i.e. fasting blood glucose
126 mg/dl or greater and/or abnormal response to an oral
glucose tolerance test. T1AM concentration was significantly higher in these patients than in the other, nondiabetic, group A patients (n ⫽ 18) (0.232 ⫾ 0.014 vs.
0.203 ⫾ 0.006 pmol/ml, P ⫽ 0.044), whereas no significant difference was observed for all the other variables,
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Galli et al.
T1AM in Human Blood
J Clin Endocrinol Metab, January 2012, 97(1):E69 –E74
between T1AM concentration and
BNP became very close (r ⫽ 0.925,
P ⫽ 0.027).
Discussion
Exogenous T1AM produces a wide array of functional effects, which are often opposite those produced on a longer
time scale by thyroid hormone (1–10).
Because T1AM could be detected in animal tissues and blood, the concept that
it is a novel chemical messenger developed, leading to speculations about its
potential physiological and pathophysiological role. However, the presence of
T1AM in human blood has been disputed (17). To clarify this crucial issue,
we studied a small series of consecutive
patients admitted to a cardiological
ward, using a novel HPLC-MS/MS
method, which has previously allowed
T1AM detection in rat blood and tissue
homogenates, as well as in a single huFIG. 1. The upper panel (A) shows a representative selected reaction monitoring
man blood sample (16).
chromatogram obtained in one patient. The peaks represent the following transitions: m/z
T1AM was detected in all patients,
356.2 3 212.2 (T1AM, peak at 2.41 min, expanded 100-fold), 651.8 3 605.8 (T3, peak at
3.41 min, expanded 10-fold), and m/z 777.8 3 731.9 (T4, peak at 3.66 min). Peak identity
and its concentration averaged 0.219
was confirmed by analyzing two additional transitions and by comparison with the
pmol/ml, which is similar to the concorresponding internal standards (not shown in this figure). The lower panels include scatter
centration that we have previously
plots showing the correlation between T1AM and selected variables, namely T4 (n ⫽ 42) (B);
measured in rat serum (18), and about
HBA1c (n ⫽ 23) (C); BNP (n ⫽ 19) (D); and ␥GT (n ⫽ 23) (E). Please note that some laboratory
data were not available in all patients. Statistical analysis was performed by linear regression
1 order of magnitude lower than serum
and the results are shown in the panels.
T3. With our method, greater than 90%
recovery of exogenous T1AM, T3, or T4
except for fasting blood glucose (157 ⫾ 15 vs. 103 ⫾ 4 added to human blood samples or rat tissue homogenates
mg/dl, P ⬍ 0.001) and glycated hemoglobin (7.08 ⫾ 0.35 was observed (18), and the values that we measured for T
3
vs. 5.42 ⫾ 0.07%, P ⬍ 0.001).
and T4 are similar to the total T3 and T4 values, which are
BNP is used as an endocrine marker of heart failure, and usually obtained by conventional techniques (19). Thereprogressive increase in BNP is considered as an index of
fore, we believe that our HPLC-MS/MS assay provides a
the progression of heart failure. In group A, six patients
measurement of total T3 and T4 concentrations and specshowed evidence of cardiac dysfunction on the basis of an
ulate that the same may happen for T1AM.
echocardiographic left ventricular ejection fraction less
However, it should be acknowledged that we are still
than 50%. If cardiac dysfunction patients were compared
unable to evaluate T1AM binding to proteins and to diswith the other group A patients (n ⫽ 19), the former
showed higher values of heart rate (91 ⫾ 5 vs. 63 ⫾ 2 beats criminate free and bound T1AM. In a recent report, Hoefig
per minute, P ⬍ 0.001), left ventricle end diastolic volume et al. (20) described a chemiluminescent immunoassay
(183 ⫾ 14 vs. 103 ⫾ 6 ml, P ⬍ 0.001), left ventricle ejec- that confirmed the presence of T1AM in human blood but
tion fraction (41.5 ⫾ 3.3 vs. 58.7 ⫾ 0.7%, P ⬍ 0.001), and provided estimated values on the order of 66 pmol/ml.
left ventricle mass (264 ⫾ 23 vs. 207 ⫾ 11 g, P ⫽ 0.021), Further investigations will be required to understand the
but no significant difference was observed for all the other reasons for this discrepancy. Immunological methods
variables, including T1AM concentration (0.209 ⫾ 0.021 raise questions about the specificity of the antibody and its
vs. 0.212 ⫾ 0.005 pmol/ml). However, within the pa- relative affinity for free vs. protein-bound antigens. In partients with reduced cardiac function, the correlation ticular, cross-reactivity might exist with endogenous
J Clin Endocrinol Metab, January 2012, 97(1):E69 –E74
T1AM derivatives, such as sulfated T1AM, and serum
might contain a mixture of T1AM and chemically modified T1AM, with equilibrium largely favoring modified
T1AM (21). Mass spectrometry-based methods are usually considered as a gold standard for specificity, but quantification from biological matrices is critically dependent
on the sample preparation steps, and we cannot exclude
that a fraction of tightly-bound T1AM is not released by
our extraction procedure.
In this initial investigation, the available routine laboratory data were used to identify potential determinants of
T1AM concentration. A significant correlation was observed between T1AM and T4, T3, FT4, or FT3. Although
the Architect FT4 assay (Abbott Diagnostics) may not be
completely reliable because its results have been shown
not to correlate with logTSH (22), our findings are consistent with the hypothesis that T1AM is produced by decarboxylation and deiodination of T4 in peripheral tissues.
In rats the highest levels of endogenous T1AM were detected in liver (18). Because increased plasma ␥GT is regarded as an index of hepatocyte injury and/or cholestasis,
the correlation between T1AM and plasma ␥GT might
reflect T1AM release from hepatocytes.
T1AM concentration was significantly increased in diabetic patients and significantly correlated with HbA1c
levels. Exogenous T1AM administration has been reported to stimulate fatty acid oxidation vs. glucose oxidation (11) and to favor glucagon secretion over insulin
secretion (12, 13). These observations suggest that endogenous T1AM might play a role in insulin resistance and in
type 2 diabetes. Our series is too small to draw further
conclusions, although the existence of a positive correlation between T1AM and BNP suggests that the relationship between T1AM and heart failure deserves further attention, even if no significant change in T1AM
concentration occurred in patients with impaired left
ventricular function.
In conclusion, T1AM is an endogenous substance that
can be consistently assayed in human blood. This pilot
investigation is consistent with peripheral production of
T1AM from thyroid hormone and suggests a potential role
of T1AM in insulin resistance.
Acknowledgments
Address all correspondence and requests for reprints to: R. Zucchi,
M.D., Dipartmento di Scienze dell’Uomo e dell’Ambiente, via
Roma 55, 56126 Pisa, Italy. E-mail: [email protected].
This work was supported by the Ministero dell’Università e
della Ricerca, Italy (Cofin 2008, to R.Z.) and by the AmbiSEN
center.
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E73
Disclosure Summary: There are no conflict of interest to disclose for any author.
References
1. Scanlan TS, Suchland KL, Hart ME, Chiellini G, Huang Y, Kruzich
PJ, Frascarelli S, Crossley DA, Bunzow JR, Ronca-Testoni S, Lin ET,
Hatton D, Zucchi R, Grandy DK 2004 3-Iodothyronamine is an
endogenous and rapid-acting derivative of thyroid hormone. Nat
Med 10:638 – 642
2. Snead AN, Santos MS, Seal RP, Miyakawa M, Edwards RH, Scanlan
TS 2007 Thyronamines inhibit plasma membrane and vescicular
monoamine transport. ACS Chem Biol 2:390 –398
3. Frascarelli S, Ghelardoni S, Chiellini G, Vargiu R, Ronca-Testoni S,
Scanlan TS, Grandy DK, Zucchi R 2008 Cardiac effects of trace
amines: pharmacological characterization of trace amine associated
receptors. Eur J Pharmacol 587:231–236
4. Cumero S, Contessi S, Zucchi R, Mavelli I 2010 3-Iodothyronamine
favours IF1 release from F0F1 ATP synthase. Biochim Biophys Acta
Bioenergetics 1797(Suppl 1):29 (Abstract)
5. Ianculescu AG, Friesema EC, Visser TJ, Giacomini KM, Scanlan TS
2010 Transport of thyroid hormones is selectively inhibited by 3-iodothyronamine. Mol BioSyst 6:1403–1410
6. Zucchi R, Chiellini G, Scanlan TS, Grandy DK 2006 Trace amineassociated receptors and their ligands. Br J Pharmacol 149:967–978
7. Ianculescu AG, Scanlan TS 2010 3-iodothyronamine (T1AM): a new
chapter of thyroid hormone endocrinology? Mol BioSyst 6:1338 –
1344
8. Piehl S, Hoefig CS, Scanlan TS, Köhrle J 2011 Thyronamines—past,
present, and future. Endocr Rev 32:64 – 80
9. Chiellini G, Frascarelli S, Ghelardoni S, Carnicelli V, Tobias SC,
DeBarber A, Brogioni S, Ronca-Testoni S, Cerbai E, Grandy DK,
Scanlan TS, Zucchi R 2007 Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function.
FASEB J 21:1597–1608
10. Ghelardoni S, Suffredini S, Frascarelli S, Brogioni S, Chiellini G,
Ronca-Testoni S, Grandy DK, Scanlan TS, Cerbai E, Zucchi R 2009.
Modulation of cardiac ionic homeostasis by 3-iodothyronamine.
J Cell Mol Med 13:3082–3090
11. Braulke LJ, Klingenspor M, DeBarber A, Tobias SC, Grandy DK,
Scanlan TS, Heldmaier G 2008 3-Iodothyronamine: a novel hormone controlling the balance between glucose and lipid utilisation.
J Comp Physiol B 178:167–177
12. Regard JB, Kataoka H, Cano DA, Camerer E, Yin L, Zheng YW,
Scanlan TS, Hebrok M, Coughlin SR 2007 Probing cell type-specific
functions of Gi in vivo identifies GPCR regulators of insulin secretion. J Clin Invest 117:4034 – 4043
13. Klieverik LP, Foppen E, Ackermans MT, Serlie MJ, Sauerwein HP,
Scanlan TS, Grandy DK, Fliers E, Kalsbeek A 2009 Central effects
of thyronamines on glucose metabolism in rats. J Endocrinol 201:
377–386
14. Dhillo WS, Bewick GA, White NE, Gardiner JV, Thompson EL,
Bataveljic A, Murphy KG, Roy D, Patel NA, Scutt JN, Armstrong A,
Ghatei MA, Bloom SR 2009 The thyroid hormone derivative 3-iodothyronamine increases food intake in rodents. Diabetes Obes
Metab 11:251–260
15. Hettinger BD, Schuff K, Marks D, Scanlan TS 2010 3-Iodothyronamine (T1AM) causes weight loss in mice via reduction in food
consumption. Proc of the 14th International Thyroid Congress,
Paris, France, OC-141 (Abstract)
16. Gu J, Soldin SP, Soldin SJ 2010 Development and validation of an
isotope dilution tandem mass spectrometry method for simultaneous quantification of 3-iodothyronamine, thyroxine, triiodothyronine, and 3,3⬘-diiodo-L-thyronine. Clin Chem 56:A60 (Abstract).
17. Ackermans MT, Klieverik LP, Ringeling P, Endert E, Kalsbeek A,
E74
Galli et al.
T1AM in Human Blood
J Clin Endocrinol Metab, January 2012, 97(1):E69 –E74
Fliers E 2010 An online solid-phase extraction-liquid chromatography-tandem mass spectrometry method to study the presence of
thyronamines in plasma and tissue and their putative conversion
from 13C6-thyroxine. J Endocrinol 206:327–334
18. Saba A, Chiellini G, Frascarelli S, Marchini M, Ghelardoni S, Raffaelli A, Tonacchera M, Vitti P, Scanlan TS, Zucchi R 2010 Tissue
distribution and cardiac metabolism of 3-iodothyronamine. Endocrinology 151:5063–5073
19. Kratzsch J, Schubert G, Pulzer F, Pfaeffle R, Koerner A, Dietz A,
Rauh M, Kiess W, Thiery J 2008 Reference intervals for TSH and
thyroid hormones are mainly affected by age, body mass index
and number of blood leucocytes, but hardly by gender and thyroid
autoantibodies during the first decades of life. Clin Biochem 41:
1091–1098
20. Hoefig CS, Köhrle J, Brabant G, Dixit K, Yap B, Strasburger CJ, Wu
Z 2011 Evidence for extrathyroidal formation of 3-iodothyronamine in humans as provided by a novel monoclonal antibodybased chemiluminescent serum immunoassay. J Clin Endocrinol
Metab 96:1864 –1872
21. Scanlan TS 2011 Endogenous 3-iodothyronamine (T1AM): more
than we bargained for. J Clin Endocrinol Metab 96:1674 –1676
22. Soldin SJ, Cheng LL, Lam LY, Werner A, Le AD, Soldin OP 2010
Comparison of FT4 with logTSH on the Abbott Architect ci8200:
pediatric reference intervals for free thyroxine and thyroid-stimulating hormone. Clin Chim Acta 411:250 –252
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