The paper by Heemstraet al.(1) in this issue ofJCEMprovides some striking and unexpected results that have significant implications for our understanding of thyroid hormone physiology in humans. Their findings help to clarify how the regulation of type 2 iodothyronine deiodinase (D2) in skeletal muscle is affected by thyroid status, fasting, and insulin, and illustrate the importance of its functional activity in that tissue. They also contribute to our understanding of the effects of illness and hypothyroidism on thyroid hormone metabolism and help define the role of skeletal muscle D2 in the production of the active hormone T3.

The iodothyronine deiodinases are a fascinating group of three selenoenzymes, two of which, the types 1 (D1) and 2 enzymes, activate T4 by removing an iodine atom from its outer or phenolic ring, converting it from an inactive prohormone to the active hormone T3. The type 3 deiodinase (D3) inactivates both T4 and T3 by removing an iodine atom from the inner (tyrosyl) ring. Unlike the case in rodents, where a large fraction of T3 is secreted directly by the thyroid, in humans 80 to 90% of the T3 is produced from T4 by these deiodinases in various tissues. The first of these enzymes to be recognized, D1, principally found in liver, kidney, and thyroid, was thought for many years to be the only outer ring deiodinase. Curiously, D1 is quite susceptible to inhibition by the antithyroid drug 6-n propylthiouracil (PTU)(2). Subsequent studies of the feedback regulation of pituitary TSH secretion by thyroid hormones revealed a second outer ring deiodinase (D2), which was insensitive to PTU, was expressed in pituitary and cerebrocortical tissue, increased in activity in response to hypothyroidism (instead of decreasing as does D1), and had different kinetic properties from D1 (3, 4). The T3 produced by D2 was especially effective in entering the nucleus and binding to thyroid hormone receptors, a property later explained by its location in the endoplasmic reticulum. D1, on the other hand, is located in the plasma membrane, and the T3 produced by this enzyme preferentially enters the plasma pool (5). Thus,