[Frontiers in Bioscience, Landmark, 25, 201-228, Jan 1, 2020]

Iodothyronine deiodinases and reduced sensitivity to thyroid hormones

Rosa Maria Paragliola1, Andrea Corsello1, Paola Concolino2, Francesca Ianni1, Giampaolo Papi1, Alfredo Pontecorvi1, Salvatore Maria Corsello1

1Endocrinology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma – Università Cattolica del Sacro Cuore, 2Institute of Biochemistry and Clinical Biochemistry, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Iodothyronine deiodinases
    3.1. Iodothyronine deiodinases: general overview
    3.2. Iodothyronine deiodinase activity and the regulation of negative feedback loop
4. Impaired iodothyronine deiodinase activity: a possible model of “syndrome of reduced sensitivity to thyroid hormone”
    4.1. Experimental models of impaired iodothyronine deiodinase activity: targeted disruption of DIO genes
    4.2. Iodothyronine deiodinase defects in the syndromes of reduced sensitivity to THs
    4.3. LT4 replacement therapy and iodothyronine deiodinase polymorphisms
5. Conclusions
6. Acknowledgment
7. References

1. ABSTRACT

Iodothyronine deiodinases are selenoproteins that regulate thyroid hormone metabolism. Of the three types of deiodinases, type 2 is the major regulator of intracellular triiodothyronine concentration in both the hypothalamus and pituitary, and therefore the major regulator of thyrotropin secretion. A defect in iodothyronine deiodinase activity can lead to a reduced sensitivity to thyroid hormones action and the most recent literature includes these defects in the so-called “syndromes of reduced sensitivity to thyroid hormones”. To date, the pathogenic variants of the selenocysteine insertion sequence-binding protein 2 (SECISBP2) gene are the first and only inherited disorder of iodothyronine metabolism described. Moreover, there is a growing interest in understanding the possible role of polymorphisms of DIO1 and DIO2 genes in some pathological conditions and in determining the requirement of levothyroxine replacement and the role of combined levothyroxine-liothyronine therapy in carrying subjects affected by hypothyroidism and who need replacement therapy. Results on this topic are still conflicting and more studies are needed to assess the efficacy of combined levothyroxine-liothyronine replacement therapy in this subset of patients.

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Abbreviations: alfa-melanocortin-stimulating hormone: alfa-MSH, Agouti-related peptide: AgRP, Differentiated thyroid cancer: DTC, Hypothalamus-pituitary-thyroid: HPT, L-amino acid transporters: LATS, Lipopolysaccharide: LPS, Loss of heterozygosity: LOH, Monocarboxylate transporters: MCT, Neuropeptide Y: NPY, Non-thyroidal illness syndrome: NTIS, Paraventricular nucleus: PVN, Peroxisome proliferator-activated receptor: PPAR, Phosphatidylinositol 3-OH kinase: PI3K, Pituitary adenylate cyclase-activating polypeptide: PACAP, Pituitary transforming gene: PTTG, Propylthiouracil: PTU, Resistance to thyroid hormone: RTH, Retinoid X receptors: RXR, Reverse T3: rT3, Selenocysteine insertion sequence-binding protein 2: SECISBP2 or SBP2, Selenocysteine-specific elongation factor tRNA: tRNASec, Selenocysteine-specific elongation factor: EFSec, Single nucleotide polymorphisms: SNPs, Thyroid hormone receptor alfa gene: THRA, Thyroid hormone receptor beta gene: THRB, Thyroid hormone receptors: TRs, Thyroid hormones: THs, Thyroid response elements: TREs, Thyrotropin: TSH, Thyrotropin-releasing hormone: TRH, Thyroxine: T4, Transporters of organic anions: OATPs, Triiodothyronine: T3, Type 1 iodothyronine deiodinase: D1, Type 2 iodothyronine deiodinase: D2, Type 3 iodothyronine deiodinase: D3, Wild-type: WT

Key Words: Iodothyronine Deiodinases, Thyroid Hormone, Hypothalamus–Pituitary–Thyroid Axis, SECISBP2, DIO Polymorphism, Reduced Sensitivity To Thyroid Hormone, Review

Send correspondence to: Salvatore M. Corsello, Largo Gemelli 8, I 00168, Rome, Italy, Tel: -39063219418, Fax: 39-0632500063, E-mail: salvatore.corsello@unicatt.it