Fig. 1 |. Roles of the DIO1 and DIO2 pathways in the TSH feedback mechanism during treatment with levothyroxine.

Levothyroxine is converted into triiodothyronine (T₃) by the action of type 1 deiodinase (DIO1) and type 2 diodinase (DIO2). T₃ produced in DIO1-expressing tissues (such as the liver) rapidly returns to the circulation, whereas T₃ produced in DIO2-expressing tissues (such as the brain, pituitary and adipose tissue) remains in the tissue longer and stimulates local thyroid hormone signalling. Conversion of levothyroxine or thyroxine (T₄) to T₃ triggers the ubiquitination of DIO2 and its destruction by the proteasome. Serum levels of T₄ are detected by the medial basal hypothalamus (MBH)–pituitary unit. Tanycytes within the MBH express high levels of DIO2, allowing them to convert T₄ into T₃, which then suppresses thyroid-stimulating hormone (TSH) secretion from the thyroid and thyrotropin releasing hormone (TRH) secretion from TRH neurons. ER, endoplasmic reticulum; Ub, ubiquitin. WSB1 is a subunit of ubiquitin ligase. FIGURE 1 adapted with permission from REF.¹²⁸, Mary Ann Liebert Inc.