Iodothyronine deiodinases: biological roles and clinical implications

Iodothyronine deiodinases (DIOs) are key regulators of thyroid hormone action. Three types of DIOs, including type 1 (D1), 2 (D2), and 3 (D3), coordinate the local and systemic availability of T3. D2 primarily catalyzes the activating conversion of T4 to T3, whereas D3 mainly catalyzes the inactivating conversion of T4 to reverse T3 (rT3) and T3 to diiodothyronine (T2). D1 has a relatively low affinity for T4 and contributes less to T4 activation but preferentially catalyzes the conversion of rT3 to T2. Thyroid hormones promote D1 and D3 expression, whereas D2 activity is transcriptionally regulated via several pathways such as cAMP and post-translationally through ubiquitin-dependent proteasomal degradation. Evidence from knockout and overexpressing mouse models and human genetic variants has clarified the physiological roles of DIOs in thyroid hormone economy. Reduced D1 activity increases serum rT3 levels, D2 enhances local thyroid hormone action and contributes to circulating T3 production, and D3 decreases circulating T3 and T4 levels while increasing rT3 levels. DIO dysregulation is implicated in several clinical conditions. GH-related disorders potentially alter thyroid function via D2-mediated mechanisms. In adrenal insufficiency, thyroid function may exhibit elevated serum fT3 levels without TSH suppression. Additionally, resistance to thyroid hormone β can be associated with bezafibrate-induced consumptive hypothyroidism through increased hepatic D3 expression. This review summarizes current knowledge on the biological properties and clinical implications of DIOs and highlights their significant role in the regulation of thyroid hormone action.