Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans

The relative roles of the types 1 and 2 iodothyronine deiodinases (D1 and D2) in extrathyroidal 3,5,3'-triiodothyronine (T-3) production in humans are unknown. We calculated the rate of thyroxine (T-4) to T-3 conversion by intact cells transiently expressing D1 or D2 at low (2 pM), normal (20 pM), and high (200 pM) free T-4 concentrations. Deiodinase activities were then assayed in cell sonicates. The ratio of T-3 production in cell sonicates (catalytic efficiency) was multiplied by the tissue activities reported in human liver (D1) and skeletal muscle (D2). From these calculations, we predict that in euthyroid humans, D2-generated T-3 is 29 nmol/d, while that of D1-generated T-3 is 15 nmol/d, from these major deiodinase-expressing tissues. The total estimated extrathyroidal T-3 production, 44 nmol/d, is in close agreement with the 40 nmol T-3/d based on previous kinetic studies. D2-generated T-3 production accounts for approximately 71% of the peripheral T-3 production in hypothyroidism, but D1 for approximately 67% in thyrotoxic patients. We also show that the intracellular D2-generated T-3 has a greater effect on T-3-dependent gene transcription than that from D1, which indicates that generation of nuclear T-3 is an intrinsic property of the D2 protein. We suggest that impairment of D-2-generated T-3 is the major cause of the reduced T-3 production in the euthyroid sick syndrome.