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.

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 thyroidectomized 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.

• Thyroid Diseases
• Thyroidectomy
• Replacement Thyroid Hormone Therapy
• Near Total Thyroidectomy

• Drug: Liothyronine (T3)
  N/A
• Drug: Levothyroxine (T4)
  N/A

• 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.
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• 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.
• Celi FS, Zemskova M, Linderman JD, Smith S, Drinkard B, Sachdev V, Skarulis MC, Kozlosky M, Csako G, Costello R, Pucino F. Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus levothyroxine. J Clin Endocrinol Metab. 2011 Nov;96(11):3466-74. Epub 2011 Aug 24.
• Celi FS, Zemskova M, Linderman JD, Babar NI, Skarulis MC, Csako G, Wesley R, Costello R, Penzak SR, Pucino F. The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized, double blind, cross-over study in thyroidectomized patients. Clin Endocrinol (Oxf). 2010 May;72(5):709-15.

• 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.

EXCLUSION CRITERIA:

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 thyroidectomy).

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, oxycodone, nitroglycerin.

Pregnancy or unwillingness to use non-hormonal contraception during the study.

Breastfeeding

Use of hormonal contraceptives or estrogen replacement therapy.

Use of tobacco (smoking, chewing) for the two weeks preceding the hospital admissions (metabolic testing)

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 antilipemic therapy.

Liver disease or ALT serum level greater than two fold the upper laboratory reference limit.

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, arthropathy).