Thyroid and Glucose and Energy Metabolism
Information source: National Institutes of Health Clinical Center (CC)
Information obtained from ClinicalTrials.gov on February 07, 2013
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Thyroid Diseases; Thyroidectomy; Replacement Thyroid Hormone Therapy; Near Total Thyroidectomy
Intervention: Liothyronine (T3) (Drug); Levothyroxine (T4) (Drug)
Phase: Phase 2
Sponsored by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Official(s) and/or principal investigator(s):
Francesco S Celi, M.D., Principal Investigator, Affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Joyce D Linderman, R.N., Phone: (301) 451-7006, Email: email@example.com
This study will examine how two thyroid preparations-levothyroxine (T4) and liothyronine
(T3)-affect fat and cholesterol metabolism, blood sugar regulation, and thyrotropin
secretion in patients who have had their thyroid gland removed. Results of the study may
help in the development of better therapies to optimize blood sugar and cholesterol levels
in some patients.
Patients 18 years of age or older who have had most or all of their thyroid gland removed
and are taking long-term thyroid hormone medication may be eligible for this study.
Candidates are screened with a medical history and physical examination, blood tests,
electrocardiogram (EKG) and neck ultrasound to visualize any remaining thyroid tissue.
At the first clinic visit, participants have blood tests, an echocardiogram (ultrasound test
to assess heart function), and vascular endothelial function evaluation (test using
nitroglycerin, a medicine given to patients having chest pain or a heart attack, and
ultrasound to measure blood vessel dilation). They are then randomly assigned to take either
T4 or T3 thyroid hormone medication. After 10 days, patients return to the hospital for a
checkup and blood test, and to complete questionnaires about their feeling of well-being and
eating habits. Thyroid medications are adjusted, if needed. Follow-up visits are scheduled
until the patient's thyroid hormone levels are have stabilized and they have maintained the
same dose for at least 30 days.
Patients are then hospitalized for 5 days for the following tests and procedures:
- Blood tests to analyze thyroid hormones, lipids, glucose, electrolytes, clotting
factors, kidney function, red cells, and DNA. (Day 1)
- DEXA scan (an x-ray test) to determine percentage of body fat tissue. (Day 1)
- Thyrotropin releasing hormone (TRH) stimulation test to indicate how well the body
responds to T4 or T3: A small amount (5 micrograms) of TRH is injected into a vein,
causing the release of another hormone called thyrotrophic stimulating hormone. Blood
samples are collected immediately before and after the TRH injections. This test is
done three times over 3 days with increasing doses of TRH. (Days 1, 2, and 3)
- Subcutaneous fat tissue microdialysis to understand how T3 and T4 affect the activity
of fat tissue. The medication isoproterenol is injected in fat tissue under the skin of
the abdomen, and fluid samples are collected from the area over a 2-hour period using
the same small needle. (Day 2)
- Cardiovascular tests, including exercise stress test using a stationary bicycle; and
repeat echocardiogram, EKG, and vascular endothelial function evaluation. (Day 3)
- Questionnaires on well being and eating habits. (Day 3)
- Euglycemic-hyperinsulinemic clamp to measure the effects of insulin. Catheters (plastic
tubes) are placed in a vein in one arm and in the hand on the opposite side of the
body. Insulin is infused through the catheter in the arm. Glucose is measured every 5
minutes from the catheter in the hand and given through the catheter in the arm to
maintain levels in the normal range. (Day 4,)
- Indirect calorimetry to study how the body uses sugar to generate energy. During the
euglycemic-hyperinsulinemic clamp test a plastic transparent hood is placed over the
head to collect the air breathed.
- Skeletal muscle biopsy to find out how T3 and T4 affect muscle strength and its ability
to store glucose. Under local anesthesia, a small piece of muscle tissue is surgically
removed. This test is optional. (Day 5)
- Fat tissue biopsy to find out how T3 and T4 affect fat tissue size and its ability to
store glucose. Under local anesthesia, a small piece of fat tissue in the abdomen is
surgically removed. This test is optional. (Day 5)
At the conclusion of these tests, patients are discharged from the hospital and enter the
second phase of the study, in which all the procedures described above, from thyroid
stabilization through the 5-day hospitalization, are repeated. This time, however, patients
who were taking T3 now take T4, and vice versa. The time interval between the two
hospitalizations depends on how quickly the thyroid hormone medical dose can be adjusted.
Official title: Peripheral Thyroid Hormone Conversion and Glucose and Energy Metabolism
Study design: Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator)
Primary outcome: Insulin-mediated glucose disposal.
Secondary outcome: Cholesterol, triglycerides and apolipoproteins; Energy expenditure by indirect calorimetry; Muscle strength by graded exercise tolerance test; and Cardiovascular function by echocardiogram, and vascular endothelial function.
Thyroid hormone action plays an important role in the regulation of many physiologic
processes, among them glucose and lipid metabolism. Interestingly, the clinical presentation
of thyroid dysfunction is extremely variable, with relatively poor correlation between
circulating hormone levels and clinical features. This finding suggests that the local,
intracellular concentration of the active hormone liothyronine (T3), regulated by peripheral
conversion of the pro-hormone levothyroxine (T4), is an important determinant in the
maintenance of the thyroidal homeostasis.
The aim of the present study is the evaluation of the role of peripheral thyroid hormone
conversion in the regulation of glucose and lipid metabolism by assessing the differential
response to T4 or T3 treatment in subjects devoid of endogenous thyroid hormone production.
T3 administration bypasses peripheral metabolism and therefore will allow us to assess the
role of the peripheral thyroid hormone conversion in the regulation of the hormone action at
the end-organ level.
Fifty hypothyroid subjects will be initially randomized to either of the thyroid hormone
replacements liothyronine (T3) or levothyroxine (T4), aimed to maintain serum TSH levels
greater than or equal to 0. 5 less than or equal to 1. 5 mU/L, indicating full replacement.
After a 30-day period of steady-state replacement the study subjects will be admitted to the
Clinical Center and, after a three-day period of stabilization and an overnight fast, will
undergo the following tests: escalating dose TRH stimulation test, indirect calorimetry,
graded exercise tolerance test, DEXA scan, and echocardiogram.
Patients will also undergo skeletal muscle biopsy and subcutaneous adipose tissue biopsy and
microdialysis, as well as a two-step euglycemic hyperinsulinemic clamp with measurement of
splanchnic gluconeogenesis. Fasting venous blood samples will be collected for the
determination of the parameters of lipid, glucose and energy metabolism. After discharge,
the patients will switch to the other form of thyroid hormone replacement therapy. The
therapy will be adjusted in order to achieve the same therapeutic goal for TSH
concentrations (greater than or equal to 0. 5 less than or equal to 1. 5 mU/L), analogous to
that achieved during the first phase of the study (TSH less than or equal to 0. 5 mU/L
difference between T3 and T4 phases). After reaching a 30-day period of steady-state
replacement, study subjects will be re-admitted to the Clinical Center and the previously
described procedures will be repeated.
Minimum age: 18 Years.
Maximum age: 65 Years.
- INCLUSION CRITERIA:
Age greater than or equal to 18 years, male or female.
History of total or near total thyroidectomy or hypothyroidism on replacement therapy.
For non-thyroidectomized patients, at least three-year history of replacement therapy (at
least 1. 2 mcg/Kg LT4/body weight), and less than 5% uptake at 24H on (123)I thyroid scan
while on replacement therapy.
Written informed consent.
BMI less than or equal to 20 or greater than or equal to 30 kg/m(2).
Metastatic thyroid cancer or history of thyroid cancer with high risk of recurrence
requiring suppressive thyroid hormone therapy (Singer 1996).
Significant thyroid residual greater than 1 mL as measured by ultrasound (limited to
thyroidectomized patients) or greater than 5 percent uptake at 24H on (123)I thyroid scan
while on replacement therapy (limited to hypothyroid patients not undergone total
History or symptoms compatible with cardiovascular disease, including paroxysmal
supraventricular tachycardia, atrial fibrillation, syncopal episodes or use of
prescription medications for heart conditions, including antihypertensives.
Allergy to lidocaine, isoproterenol, TRH, levothyroxine, liothyronine, Tylenol #3,
Pregnancy or unwillingness to use non-hormonal contraception during the study.
Use of hormonal contraceptives or estrogen replacement therapy.
Use of tobacco (smoking, chewing) for the two weeks preceding the hospital admissions
Diabetes mellitus, either type I or II.
Hypercholesterolemia (serum levels greater than or equal to 240 mg/dL),
hypertriglyceridemia (plasma levels greater than or equal to 220 mg/dL) and/or use of
Liver disease or ALT serum level greater than two fold the upper laboratory reference
Renal insufficiency or estimated creatinine clearance less than or equal to 50 mL/min.
Use of medications/supplements/alternative therapies known to alter thyroid function.
Current history or symptoms compatible with psychosis including major depression
(including history of hospitalization for depression, history of attempted suicide,
history of suicidal ideation).
Use of antipsychotic medications
History of drug or alcohol abuse within the last 5 years; current use of drugs or alcohol
(CAGE greater than 3).
Keloid formation (relative to skeletal muscle and subcutaneous adipose tissue biopsies).
Current or previous clinically significant (requiring medical/surgical intervention)
extrathyroidal manifestations of autoimmune thyroid disease (dermopathy, ophthalmopathy,
Locations and Contacts
Joyce D Linderman, R.N., Phone: (301) 451-7006, Email: firstname.lastname@example.org
National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting
For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL), Phone: 800-411-1222, Ext: TTY8664111010, Email: email@example.com
NIH Clinical Center Detailed Web Page
Arner P, Bolinder J, Wennlund A, Ostman J. Influence of thyroid hormone level on insulin action in human adipose tissue. Diabetes. 1984 Apr;33(4):369-75.
Bakker SJ, ter Maaten JC, Popp-Snijders C, Slaets JP, Heine RJ, Gans RO. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects. J Clin Endocrinol Metab. 2001 Mar;86(3):1206-11.
Bartha T, Kim SW, Salvatore D, Gereben B, Tu HM, Harney JW, Rudas P, Larsen PR. Characterization of the 5'-flanking and 5'-untranslated regions of the cyclic adenosine 3',5'-monophosphate-responsive human type 2 iodothyronine deiodinase gene. Endocrinology. 2000 Jan;141(1):229-37.
Starting date: March 2005
Last updated: January 9, 2013