Thyroid and Glucose and Energy Metabolism
Condition: Thyroid Diseases
MeSH terms: Thyroid Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      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 after
      screening.
    

Detailed description: 
      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) treatment period (one arm cross-over
      design, with treatment sequence randomized), 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 (second period) . 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 evaluation procedures will be repeated.
    

Intervention name(s): Liothyronine and Levothyroxine
Intervention type(s): Drug
Intervention description(s): Hypothyroid patients are treated with Liothyronine and Levothyroxine in 2 crossover, randomized phases
Other intervention name(s): T3 and T4
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Keywords: Levothyroxine; Liothyronine; Lipid Metabolism; Gluconeogensis; Thyrotropin Releasing Hormone; Deiodinase; Replacement Thyroid Hormone Therapy; Thyroidectomy; Near Total Thyroidectomy