Thyroid and Glucose and Energy Metabolism
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.
Replacement Thyroid Hormone Therapy
Near Total Thyroidectomy
Drug: Liothyronine (T3)
Drug: Levothyroxine (T4)
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
|Official Title:||Peripheral Thyroid Hormone Conversion and Glucose and Energy Metabolism|
- Insulin-mediated glucose disposal. [ Time Frame: One month of therapy. ] [ Designated as safety issue: No ]
- 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. [ Time Frame: One month of therapy. ] [ Designated as safety issue: No ]
|Study Start Date:||March 2005|
|Study Completion Date:||November 2013|
|Primary Completion Date:||November 2013 (Final data collection date for primary outcome measure)|
Drug: Liothyronine (T3)
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00106119
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Francesco S Celi, M.D.||National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)|