Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans.
Level 5 - mechanism / opinion, no new human data
Mechanism-based reasoning and in vitro kinetic modeling using cell assays and historical human tissue data.
PubMed 16127464 · doi:10.1172/JCI25083
What was done
Researchers measured thyroxine (T4) to triiodothyronine (T3) conversion rates in intact cells transiently expressing human type 1 (D1) or type 2 (D2) iodothyronine deiodinase exposed to low (2 pM), normal (20 pM), and high (200 pM) free T4 concentrations. Deiodinase activities were assayed in cell sonicates. Catalytic efficiency ratios were combined with historical human liver (D1) and skeletal muscle (D2) tissue activity measurements to calculate daily peripheral T3 production in euthyroid, hypothyroid, and thyrotoxic states. They also compared the effect of intracellular D1- versus D2-generated T3 on T3-dependent gene transcription.
What was found
In euthyroid humans, calculated peripheral T3 production was 29 nmol/d from D2 and 15 nmol/d from D1, yielding an estimated total extrathyroidal production of 44 nmol/d (comparable to previous kinetic estimates of 40 nmol/d). D2-generated T3 accounted for approximately 71% of peripheral T3 production in hypothyroidism, whereas D1 accounted for approximately 67% in thyrotoxicosis. Intracellular D2-generated T3 exerted a greater effect on T3-dependent gene transcription than D1-generated T3.
Why it matters
This work overturned the prevailing model that D1 is the primary source of circulating T3 in humans, identifying D2 as the principal driver of daily plasma T3 production and intracellular nuclear receptor activation.
Limits
The conclusions derive from in vitro cell models and mathematical extrapolations based on historical tissue activity data rather than direct in vivo human tracer measurements. Tissue models focused strictly on liver (D1) and skeletal muscle (D2), without direct quantification of contributions from other organs. No participant sample size was reported.
Cited by
- supports Active skeletal muscle is a major site for the conversion of T4 into active T3.