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

Abstract

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 D2-generated T 3 is the major cause of the reduced T 3 production in the euthyroid sick syndrome. IntroductionThe monodeiodination of thyroxine (T 4 ) to 3,5,3′-triiodothyronine (T 3 ) activates the major secretory product of the iodine-sufficient human thyroid gland, producing approximately 80% of the circulating T 3 in humans. The types 1 and 2 iodothyronine deiodinases (D1 and D2) are members of a family of oxidoreductases that catalyze this reaction (1). These integral membrane proteins contain the rare amino acid selenocysteine (encoded by a UGA) in their active site. Both D1 and D2 require an as-yet-unidentified cofactor for the reaction. Several decades ago, D1 was identified in the liver and the kidney of rats and humans, and it is often assumed that this enzyme is the source of most of the plasma T 3 in humans. The more recent discovery of D2 mRNA and activity in human skeletal muscle suggests that D2 could also be a significant source for plasma T 3 production in humans, but this has not been quantitatively defined (1).The biochemical and molecular properties of D2 seem ideal for extrathyroidal T 3 production. Its activity is tightly controlled by the concentration of its preferred substrate, T 4 , since catalysis accelerates the ubiquitination of this enzyme, inactivating it and accelerating its degradation in proteasomes (2). The half-life of D2 in normal cells is 20-30 minutes in the presence of T 4 . The transcription of the type 2 deiodinase (DIO2) gene is also negatively regulated by T 3 (3). In contrast, the D1 protein has a long half-life (>12 hours), and the transcription of the human type 1 deiodinase (DIO1) gene is markedly stimulated by T 3 , just the opposite of what would be expected in a typical feedba...

Type 1 and type 2 iodothyronine deiodinases in the thyroid gland of patients with 3,5,3′-triiodothyronine-predominant Graves' disease

“…Maia et al (21) estimated that D2 is the major contributor of extrathyroidal T 3 production in euthyroid subjects, and peripheral T 3 production may switch from D2 to D1 dependency in thyrotoxic patients, since the D2 activity decreases due to the posttranslational substrate-induced inactivation of D2 (20,21). In this study, since the serum FT 4 level in the patients with T 3 -P-GD was within the normal range, we considered that D2-generated T 3 mainly contributes to the extrathyroidal T 3 production in the patients with T 3 -P-GD.…”

Subclinical hypothyroidism is an independent predictor of adverse cardiovascular outcomes in patients with acute decompensated heart failure

“…More than 80% of T3, which is considered to be the biologically active form of thyroid hormones, derives from peripheral conversion of the prohormone T4 via a reaction catalyzed by 5′‐monodeiodinases in organs such as the liver, kidney, and skeletal muscle 25, 26. It has been reported that a decrease in 5′‐monodeiodination leads to low serum T3 concentration in patients with any severe systemic illness, including acute myocardial infarction,27 and chronic heart failure 8.…”

Role of thyroid hormone in skeletal muscle physiology

“…In 2005, it was postulated that SM could participate in the regulation of serum T 3 levels since SM is wildly distributed and has a large mass (Maia et al 2005). However, global D2KO mice have normal levels of T 3 and increased levels of T 4 and TSH (Schneider et al 2001).…”