The relative roles of the types 1 and 2 iodothyronine deiodinases (D1 and D2) in 
extrathyroidal 3,5,3'-triiodothyronine (T3) production in humans are unknown. We 
calculated the rate of thyroxine (T4) to T3 conversion by intact cells 
transiently expressing D1 or D2 at low (2 pM), normal (20 pM), and high (200 pM) 
free T4 concentrations. Deiodinase activities were then assayed in cell 
sonicates. The ratio of T3 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 T3 is 29 nmol/d, while that of D1-generated T3 is 15 
nmol/d, from these major deiodinase-expressing tissues. The total estimated 
extrathyroidal T3 production, 44 nmol/d, is in close agreement with the 40 nmol 
T3/d based on previous kinetic studies. D2-generated T3 production accounts for 
approximately 71% of the peripheral T3 production in hypothyroidism, but D1 for 
approximately 67% in thyrotoxic patients. We also show that the intracellular 
D2-generated T3 has a greater effect on T3-dependent gene transcription than 
that from D1, which indicates that generation of nuclear T3 is an intrinsic 
property of the D2 protein. We suggest that impairment of D2-generated T3 is the 
major cause of the reduced T3 production in the euthyroid sick syndrome.