Journal of Endocrinological Investigation

, Volume 34, Issue 5, pp 395–407

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

  • A. Marsili
  • A. M. Zavacki
  • J. W. Harney
  • P. R. Larsen
Review Article


T4 is a prohormone secreted by the thyroid. T4 has a long half life in circulation and it is tightly regulated to remain constant in a variety of circumstances. However, the availability of iodothyronine selenodeiodinases allow both the initiation or the cessation of thyroid hormone action and can result in surprisingly acute changes in the intracellular concentration of the active hormone T3, in a tissue-specific and chronologically-determined fashion, in spite of the constant circulating levels of the prohormone. This fine-tuning of thyroid hormone signaling is becoming widely appreciated in the context of situations where the rapid modifications in intracellular T3 concentrations are necessary for developmental changes or tissue repair. Given the increasing availability of genetic models of deiodinase deficiency, new insights into the role of these important enzymes are being recognized. In this review, we have incorporated new information regarding the special role played by these enzymes into our current knowledge of thyroid physiology, emphasizing the clinical significance of these new insights.


Deiodinase hyperthyroidism hypothyroidism iodine nonthyroidal illness selenium selenoprotein thyroid hormone metabolism thyroid hormone action thyroxine triiodothyronine TSH 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Berry MJ, Maia AL, Kieffer JD, Harney JW, Larsen PR. Substitution of cysteine for selenocysteine in type I iodothyronine deiodinase reduces the catalytic efficiency of the protein but enhances its translation. Endocrinology 1992, 131: 1848–52.PubMedGoogle Scholar
  2. 2.
    Berry MJ, Banu L, Chen YY, et al. Recognition of UGA as a selenocysteine codon in type I deiodinase requires sequences in the 3′ untranslated region. Nature 1991, 353: 273–6.PubMedGoogle Scholar
  3. 3.
    Berry MJ. Knowing when not to stop. Nat Struct Mol Biol 2005, 12: 389–90.PubMedGoogle Scholar
  4. 4.
    Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 2002, 23: 38–89.PubMedGoogle Scholar
  5. 5.
    Gereben B, Zavacki AM, Ribich S, et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 2008, 29: 898–938.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Silva JE, Larsen PR Pituitary nuclear 3,5,3′-triiodothyronine and thyrotropin secretion: an explanation for the effect of thyroxine. Science 1977, 198: 617–20.PubMedGoogle Scholar
  7. 7.
    Larsen PR. Thyroid-pituitary interaction: feedback regulation of thyrotropin secretion by thyroid hormones. N Engl J Med 1982, 306: 23–32.PubMedGoogle Scholar
  8. 8.
    Larsen PR, Dick TE, Markovitz BP, Kaplan MM, Gard TG. Inhibition of intrapituitary thyroxine to 3.5.3′-triiodothyronine conversion prevents the acute suppression of thyrotropin release by thyroxine in hypothyroid rats. J Clin Invest 1979, 64: 117–28.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Silva JE, Larsen PR. Peripheral metabolism of homologous thyrotropin in euthyroid and hypothyroid rats: acute effects of thyrotropin-releasing hormone, triiodothyronine, and thyroxine. Endocrinology 1978, 102: 1783–96.PubMedGoogle Scholar
  10. 10.
    Connors JM, Hedge GA. Feedback effectiveness of periodic versus constant triiodothyronine replacement. Endocrinology 1980, 106: 911–7.PubMedGoogle Scholar
  11. 11.
    Christoffolete MA, Ribeiro R, Singru P, et al. Atypical expression of type 2 iodothyronine deiodinase in thyrotrophs explains the thyroxine-mediated pituitary thyrotropin feedback mechanism. Endocrinology 2006, 147: 1735–43.PubMedGoogle Scholar
  12. 12.
    Larsen PR, Silva JE, Kaplan MM. Relationships between circulating and intracellular thyroid hormones: physiological and clinical implications. Endocr Rev 1981, 2: 87–102.PubMedGoogle Scholar
  13. 13.
    Schneider MJ, Fiering SN, Pallud SE, Parlow AF, St Germain DL, Galton VA. Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. Mol Endocrinol 2001, 15: 2137–48.PubMedGoogle Scholar
  14. 14.
    Segerson TP, Kauer J, Wolfe HC, et al. Thyroid hormone regulates TRH biosynthesis in the paraventricular nucleus of the rat hypothalamus. Science 1987, 238: 78–80.PubMedGoogle Scholar
  15. 15.
    Kakucska I, Rand W, Lechan RM. Thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus is dependent upon feedback regulation by both triiodothyronine and thyroxine. Endocrinology 1992, 130: 2845–50.PubMedGoogle Scholar
  16. 16.
    Riskind PN, Kolodny JM, Larsen PR. The regional hypothalamic distribution of type II 5′-monodeiodinase in euthyroid and hypothyroid rats. Brain Res 1987, 420: 194–8.PubMedGoogle Scholar
  17. 17.
    Tu HM, Kim SW, Salvatore D, et al. Regional distribution of type 2 thyroxine deiodinase messenger ribonucleic acid in rat hypothalamus and pituitary and its regulation by thyroid hormone. Endocrinology 1997, 138: 3359–68.PubMedGoogle Scholar
  18. 18.
    Izumi M, Larsen PR Triiodothyronine, thyroxine, and iodine in purified thyroglobulin from patients with Graves’ disease. J Clin Invest 1977, 59: 1105–12.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Salvatore D, Tu H, Harney JW, Larsen PR Type 2 iodothyronine deiodinase is highly expressed in human thyroid. J Clin Invest 1996, 98: 962–8.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Laurberg P. Mechanisms governing the relative proportions of thyroxine and 3,5,3′-triiodothyronine in thyroid secretion. Metabolism 1984, 33: 379–92.PubMedGoogle Scholar
  21. 21.
    Pilo A, Iervasi G, Vitek F, Ferdeghini M, Cazzuola F, Bianchi R. Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans by multicompartmental analysis. Am J Physiol 1990, 258: E715–26.PubMedGoogle Scholar
  22. 22.
    Saberi M, Sterling FH, Utiger RD. Reduction in extrathyroidal triiodothyronine production by propylthiouracil in man. J Clin Invest 1975, 55: 218–23.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Maia AL, Kim BW, Huang SA, Harney JW, Larsen PR. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. J Clin Invest 2005, 115: 2524–33.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Lum SM, Nicoloff JT, Spencer CA, Kaptein EM. Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man. J Clin Invest 1984, 73: 570–5.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Steinsapir J, Bianco AC, Buettner C, Harney J, Larsen PR. Substrate-induced down-regulation of human type 2 deiodinase (hD2) is mediated through proteasomal degradation and requires interaction with the enzyme’s active center. Endocrinology 2000, 141: 1127–35.PubMedGoogle Scholar
  26. 26.
    Gereben B, Goncalves C, Harney JW, Larsen PR, Bianco AC. Selective proteolysis of human type 2 deiodinase: a novel ubiquitin-proteasomal mediated mechanism for regulation of hormone activation. Mol Endocrinol 2000, 14: 1697–708.PubMedGoogle Scholar
  27. 27.
    Burmeister LA, Pachucki J, St Germain DL. Thyroid hormones inhibit type 2 iodothyronine deiodinase in the rat cerebral cortex by both pre- and posttranslational mechanisms. Endocrinology 1997, 138: 5231–7.PubMedGoogle Scholar
  28. 28.
    Silva JE, Matthews PS. Production rates and turnover of triiodothyronine in rat-developing cerebral cortex and cerebellum. Responses to hypothyroidism. J Clin Invest 1984, 74: 1035–49.Google Scholar
  29. 29.
    Peeters RP, Friesema EC, Docter R, Hennemann G, Visser TJ. Effects of thyroid state on the expression of hepatic thyroid hormone transporters in rats. Am J Physiol Endocrinol Metab 2002, 283: E1232–8.PubMedGoogle Scholar
  30. 30.
    Galton VA, Schneider MJ, Clark AS, St Germain DL. Life without thyroxine to 3,5,3′-triiodothyronine conversion: studies in mice devoid of the 5′-deiodinases. Endocrinology 2009, 150: 2957–63.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Porterfield SP, Hendrich CE. The role of thyroid hormones in prenatal and neonatal neurological development — current perspectives. Endocr Rev 1993, 14: 94–106.PubMedGoogle Scholar
  32. 32.
    Bernal J. Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab 2007, 3: 249–59.PubMedGoogle Scholar
  33. 33.
    Heuer H, Visser TJ. Minireview: Pathophysiological importance of thyroid hormone transporters. Endocrinology 2009, 150: 1078–83.PubMedGoogle Scholar
  34. 34.
    Guadano-Ferraz A, Obregon MJ, St Germain DL, Bernal J. The type 2 iodothyronine deiodinase is expressed primarily in glial cells in the neonatal rat brain. Proc Natl Acad Sci U S A 1997, 94: 10391–6.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Peeters R, Fekete C, Goncalves C, et al. Regional physiological adaptation of the central nervous system deiodinasesto iodine deficiency. Am J Physiol Endocrinol Metab 2001, 281: E54–61.PubMedGoogle Scholar
  36. 36.
    Morte B, Ceballos A, Diez D, et al. Thyroid hormone-regulated mouse cerebral cortex genes are differentially dependent on the source of the hormone: a study in monocarboxylate transporter-8- and deiodinase-2-deficient mice. Endocrinology 2010, 151: 2381–7.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Hernandez A, Quignodon L, Martinez ME, Flamant F, St Germain DL. Type 3 deiodinase deficiency causes spatial and temporal alterations in brain T3 signaling that are dissociated from serum thyroid hormone levels. Endocrinology 2010, 151: 5550–8.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Fekete C, Gereben B, Doleschall M, et al. Lipopolysaccharide induces type 2 iodothyronine deiodinase in the mediobasal hypothalamus: implications for the nonthyroidal illness syndrome. Endocrinology 2004, 145: 1649–55.PubMedGoogle Scholar
  39. 39.
    Freitas BC, Gereben B, Castillo M, et al. Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells. J Clin Invest 2010, 120: 2206–17.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Ng L, Hernandez A, He W, et al. A protective role for type 3 deiodinase, a thyroid hormone-inactivating enzyme, in cochlear development and auditory function. Endocrinology 2009, 150: 1952–60.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Campos-Barros A, Amma LL, Faris JS, et al. Type 2 iodothyronine deiodinase expression in the cochlea before the onset of hearing. Proc Natl Acad Sci U S A 2000, 97: 1287–92.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Ng L, Goodyear RJ, Woods CA, et al. Hearing loss and retarded cochlear development in mice lacking type 2 iodothyronine deiodinase. Proc Natl Acad Sci U S A 2004, 101: 3474–9.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Ng L, Lyubarsky A, Nikonov SS, et al. Type 3 deiodinase, a thyroid-hormone-inactivating enzyme, controls survival and maturation of cone photoreceptors. J Neurosci 2010, 30: 3347–57.PubMedCentralPubMedGoogle Scholar
  44. 44.
    Dentice M, Bandyopadhyay A, Gereben B, et al. The Hedgehoginducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate. Nat Cell Biol 2005, 7: 698–705.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Silva JE, Larsen PR. Adrenergic activation of triiodothyronine production in brown adipose tissue. Nature 1983, 305: 712–3.PubMedGoogle Scholar
  46. 46.
    Bianco AC, Silva JE. Intracellular conversion of thyroxine to triiodothyronine is required for the optimal thermogenic function of brown adipose tissue. J Clin Invest 1987, 79: 295–300.PubMedCentralPubMedGoogle Scholar
  47. 47.
    de Jesus LA, Carvalho SD, Ribeiro MO, et al. The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest 2001, 108: 1379–85.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Christoffolete MA, Linardi CC, de Jesus L, et al. Mice with targeted disruption of the Dio2 gene have cold-induced overexpression of the uncoupling protein 1 gene but fail to increase brown adipose tissue lipogenesis and adaptive thermogenesis. Diabetes 2004, 53: 577–84.PubMedGoogle Scholar
  49. 49.
    Watanabe M, Houten SM, Mataki C, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006, 439: 484–9.PubMedGoogle Scholar
  50. 50.
    al-Adsani H, Hoffer LJ, Silva JE. Resting energy expenditure is sensitive to small dose changes in patients on chronic thyroid hormone replacement. J Clin Endocrinol Metab 1997, 82: 1118–25.PubMedGoogle Scholar
  51. 51.
    Salvatore D, Bartha T, Harney JW, Larsen PR. Molecular biological and biochemical characterization of the human type 2 selenodeiodinase. Endocrinology 1996, 137: 3308–15.PubMedGoogle Scholar
  52. 52.
    Marsili A, Ramadan W, Harney JW, et al. Type 2 iodothyronine deiodinase levels are higher in slow-twitch than fast-twitch mouse skeletal muscle and are increased in hypothyroidism. Endocrinology 2010, 151: 5952–60.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Cypess AM, Lehman S, Williams G, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009, 360: 1509–17.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Skarulis MC, Celi FS, Mueller E, et al. Thyroid hormone induced brown adipose tissue and amelioration of diabetes in a patient with extreme insulin resistance. J Clin Endocrinol Metab 2010, 95: 256–62.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Silva JE. Thermogenic mechanisms and their hormonal regulation. Physiol Rev 2006, 86: 435–64.PubMedGoogle Scholar
  56. 56.
    Lopez M, Varela L, Vazquez MJ, et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 2010, 16: 1001–8.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Bassett JH, Boyde A, Howell PG, et al. Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts. Proc Natl Acad Sci U S A 2010, 107: 7604–9.PubMedCentralPubMedGoogle Scholar
  58. 58.
    Canani LH, Capp C, Dora JM, et al. The type 2 deiodinase A/G (Thr92Ala) polymorphism is associated with decreased enzyme velocity and increased insulin resistance in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2005, 90: 3472–8.PubMedGoogle Scholar
  59. 59.
    Heemstra KA, Hoftijzer H, van der Deure WM, et al. The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density. J Bone Miner Res 2010, 25: 1385–91.PubMedGoogle Scholar
  60. 60.
    Visser WE, Heemstra KA, Swagemakers SM, et al. Physiological thyroid hormone levels regulate numerous skeletal muscle transcripts. J Clin Endocrinol Metab 2009, 94: 3487–96.PubMedGoogle Scholar
  61. 61.
    Heemstra KA, Soeters MR, Fliers E, et al. Type 2 iodothyronine deiodinase in skeletal muscle: effects of hypothyroidism and fasting. J Clin Endocrinol Metab 2009, 94: 2144–50.PubMedGoogle Scholar
  62. 62.
    Larsen PR. Type 2 iodothyronine deiodinase in human skeletal muscle: new insights into its physiological role and regulation. J Clin Endocrinol Metab 2009, 94: 1893–5.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Muscat GE, Mynett-Johnson L, Dowhan D, Downes M, Griggs R. Activation of myoD gene transcription by 3,5,3′-triiodo-L-thyronine: a direct role for the thyroid hormone and retinoid X receptors. Nucleic Acids Res 1994, 22: 583–91.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Dentice M, Marsili A, Ambrosio R, et al. The FoxO3/type 2 deiodinase pathway is required for normal mouse myogenesis and muscle regeneration. J Clin Invest 2010, 120: 4021–30.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Olivares EL, Marassi MP, Fortunato RS, et al. Thyroid function disturbance and type 3 iodothyronine deiodinase induction after myocardial infarction in rats a time course study. Endocrinology 2007, 148: 4786–92.PubMedGoogle Scholar
  66. 66.
    Pol CJ, Muller A, Zuidwijk MJ, et al. Left-ventricular remodeling after myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition. Endocrinology 2011, 152: 669–79.PubMedGoogle Scholar
  67. 67.
    Wassen FW, Schiel AE, Kuiper GG, et al. Induction of thyroid hormone-degrading deiodinase in cardiac hypertrophy and failure. Endocrinology 2002, 143: 2812–5.PubMedGoogle Scholar
  68. 68.
    Li WW, Le Goascogne C, Ramauge M, et al. Induction of type 3 iodothyronine deiodinase by nerve injury in the rat peripheral nervous system. Endocrinology 2001, 142: 5190–7.PubMedGoogle Scholar
  69. 69.
    Simonides WS, Mulcahey MA, Redout EM, et al. Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxicischemic disease in rats. J Clin Invest 2008, 118: 975–83.PubMedCentralPubMedGoogle Scholar
  70. 70.
    Boelen A, Kwakkel J, Alkemade A, et al. Induction of type 3 deiodinase activity in inflammatory cells of mice with chronic local inflammation. Endocrinology 2005, 146: 5128–34.PubMedGoogle Scholar
  71. 71.
    Boelen A, Boorsma J, Kwakkel J, et al. Type 3 deiodinase is highly expressed in infiltrating neutrophilic granulocytes in response to acute bacterial infection. Thyroid 2008, 18: 1095–03.PubMedGoogle Scholar
  72. 72.
    Boelen A, Kwakkel J, Wieland CW, et al. Impaired bacterial clearance in type 3 deiodinase-deficient mice infected with Streptococcus pneumoniae. Endocrinology 2009, 150: 1984–90.PubMedCentralPubMedGoogle Scholar
  73. 73.
    Abuid J, Larsen PR. Triiodothyronine and thyroxine in hyperthyroidism. Comparison of the acute changes during therapy with antithyroid agents. J Clin Invest 1974, 54: 201–8.Google Scholar
  74. 74.
    Nishikawa M, Toyoda N, Yonemoto T, et al. Quantitative measurements for type 1 deiodinase messenger ribonucleic acid in human peripheral blood mononuclear cells: mechanism of the preferential increase of T3 in hyperthyroid Graves’ disease. Biochem Biophys Res Commun 1998, 250: 642–6.PubMedGoogle Scholar
  75. 75.
    Ishii H, Inada M, Tanaka K, et al. Triiodothyronine generation from thyroxine in human thyroid: enhanced conversion in Graves’ thyroid tissue. J Clin Endocrinol Metab 1981, 52: 1211–7.PubMedGoogle Scholar
  76. 76.
    Toyoda N, Nishikawa M, Horimoto M, et al. Graves’ immunoglobulin G stimulates iodothyronine 5′-deiodinating activity in FRTL-5 rat thyroid cells. J Clin Endocrinol Metab 1990, 70: 1506–11.PubMedGoogle Scholar
  77. 77.
    Geffner DL, Azukizawa M, Hershman JM. Propylthiouracil blocks extrathyroidal conversion of thyroxine to triiodothyronine and augments thyrotropin secretion in man. J Clin Invest 1975, 55: 224–9.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Laurberg P, Vestergaard H, Nielsen S, et al. Sources of circulating 3,5,3′-triiodothyronine in hyperthyroidism estimated after blocking of type 1 and type 2 iodothyronine deiodinases. J Clin Endocrinol Metab 2007, 92: 2149–56.PubMedGoogle Scholar
  79. 79.
    Ito M, Toyoda N, Nomura E, et al. Type 1 and type 2 iodothyronine deiodinases in the thyroid gland of patients with 3,5,3′-triiodothyronine-predominant Graves’ disease. EurJ Endocrinol 2011, 164: 95–100.Google Scholar
  80. 80.
    Huang SA, Tu HM, Harney JW, et al. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 2000, 343: 185–9.PubMedGoogle Scholar
  81. 81.
    Ruppe MD, Huang SA, Jan de Beur SM. Consumptive hypothyroidism caused by paraneoplastic production of type 3 iodothyronine deiodinase. Thyroid 2005, 15: 1369–72.PubMedGoogle Scholar
  82. 82.
    Huang SA, Fish SA, Dorfman DM, et al. A 21-year-old woman with consumptive hypothyroidism due to a vascular tumor expressing type 3 iodothyronine deiodinase. J Clin Endocrinol Metab 2002, 87: 4457–61.PubMedGoogle Scholar
  83. 83.
    Kim BW, Daniels GH, Harrison BJ, et al. Overexpression of type 2 iodothyronine deiodinase in follicular carcinoma as a cause of low circulating free thyroxine levels. J Clin Endocrinol Metab 2003, 88: 594–8.PubMedGoogle Scholar
  84. 84.
    Celi FS, Coppotelli G, Chidakel A, et al. The role of type 1 and type 2 5′-deiodinase in the pathophysiology of the 3,5,3′-triiodothyronine toxicosis of McCune-Albright syndrome. J Clin Endocrinol Metab 2008, 93: 2383–9.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Adler SM, Wartofsky L. The nonthyroidal illness syndrome. Endocrinol Metab Clin North Am 2007, 36: 657–72, vi.PubMedGoogle Scholar
  86. 86.
    Peeters RP, Wouters PJ, van Toor H, et al. Serum 3,3′,5′-triiodothyronine (rT3) and 3,5,3′-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab 2005, 90: 4559–65.PubMedGoogle Scholar
  87. 87.
    Yu J, Koenig RJ. Regulation of hepatocyte thyroxine 5′-deiodinase by T3 and nuclear receptor coactivators as a model of the sick euthyroid syndrome. J Biol Chem 2000, 275: 38296–301.PubMedGoogle Scholar
  88. 88.
    Debaveye Y, Ellger B, Mebis L, et al. Tissue deiodinase activity during prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone-releasing peptide-2. Endocrinology 2005, 146: 5604–11.PubMedGoogle Scholar
  89. 89.
    Rodriguez-Perez A, Palos-Paz F, Kaptein E, et al. Identification of molecular mechanisms related to nonthyroidal illness syndrome in skeletal muscle and adipose tissue from patients with septic shock. Clin Endocrinol (Oxf) 2008, 68: 821–7.Google Scholar
  90. 90.
    Mebis L, Langouche L, Visser TJ, Van den Berghe G. The type II iodothyronine deiodinase is up-regulated in skeletal muscle during prolonged critical illness. J Clin Endocrinol Metab 2007, 92: 3330–3.PubMedGoogle Scholar
  91. 91.
    Sanchez E, Singru PS, Wittmann G, et al. Contribution of TNF-alpha and nuclear factor-kappaB signaling to type 2 iodothyronine deiodinase activation in the mediobasal hypothalamus after lipopolysaccharide administration. Endocrinology 2010, 151: 3827–35.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Lamirand A, Ramauge M, Pierre M, Courtin F. Bacterial lipopolysaccharide induces type 2 deiodinase in cultured rat astrocytes. J Endocrinol 2010, 208: 183–92.PubMedGoogle Scholar
  93. 93.
    Brent GA, Hershman JM. Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration. J Clin Endocrinol Metab 1986, 63: 1–8.PubMedGoogle Scholar
  94. 94.
    Huang SA, Dorfman DM, Genest DR, Salvatore D, Larsen PR. Type 3 iodothyronine deiodinase is highly expressed in the human uteroplacental unit and in fetal epithelium. J Clin Endocrinol Metab 2003, 88: 1384–8.PubMedGoogle Scholar
  95. 95.
    Galton VA, Martinez E, Hernandez A, St Germain EA, Bates JM, St Germain DL. Pregnant rat uterus expresses high levels of the type 3 iodothyronine deiodinase. J Clin Invest 1999, 103: 979–87.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Hidal JT, Kaplan MM. Characteristics of thyroxine 5′-deiodination in cultured human placental cells. Regulation by iodothyronines. J Clin Invest 1985, 76: 947–55.PubMedCentralPubMedGoogle Scholar
  97. 97.
    Santini F, Chiovato L, Ghirri P, et al. Serum iodothyronines in the human fetus and the newborn: evidence for an important role of placenta in fetal thyroid hormone homeostasis. J Clin Endocrinol Metab 1999, 84: 493–8.PubMedGoogle Scholar
  98. 98.
    Ferreiro B, Bernal J, Goodyer CG, Branchard CL. Estimation of nuclear thyroid hormone receptor saturation in human fetal brain and lung during early gestation. J Clin Endocrinol Metab 1988, 67: 853–6.PubMedGoogle Scholar
  99. 99.
    van Wassenaer AG, Kok JH, de Vijlder JJ, et al. Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks’ gestation. N Engl J Med 1997, 336: 21–6.PubMedGoogle Scholar
  100. 100.
    Galton VA, Martinez E, Hernandez A, St Germain EA, Bates JM, St Germain DL. The type 2 iodothyronine deiodinase is expressed in the rat uterus and induced during pregnancy. Endocrinology 2001, 142: 2123–8.PubMedGoogle Scholar
  101. 101.
    Huang SA, Mulcahey MA, Crescenzi A, et al. Transforming growth factor-beta promotes inactivation of extracellular thyroid hormones via transcriptional stimulation of type 3 iodothyronine deiodinase. Mol Endocrinol 2005, 19: 3126–36.PubMedGoogle Scholar
  102. 102.
    Arafah BM. Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med 2001, 344: 1743–9.PubMedGoogle Scholar
  103. 103.
    Hernandez A, Martinez ME, Fiering S, Galton VA, St Germain D. Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J Clin Invest 2006, 116: 476–84.PubMedCentralPubMedGoogle Scholar
  104. 104.
    Hernandez A, Martinez ME, Liao XH, et al. Type 3 deiodinase deficiency results in functional abnormalities at multiple levels of the thyroid axis. Endocrinology 2007, 148: 5680–7.PubMedGoogle Scholar
  105. 105.
    Kempers MJ, van Trotsenburg AS, van Tijn DA, et al. Disturbance of the fetal thyroid hormone state has long-term consequences for treatment of thyroidal and central congenital hypothyroidism. J Clin Endocrinol Metab 2005, 90: 4094–100.PubMedGoogle Scholar
  106. 106.
    Dentice M, Ambrosio R, Salvatore D. Role of type 3 deiodinase in cancer. Expert Opin Ther Targets 2009, 13: 1363–73.PubMedGoogle Scholar
  107. 107.
    Santini F, Vitti P, Chiovato L, et al. Role for inner ring deiodination preventing transcutaneous passage of thyroxine. J Clin Endocrinol Metab 2003, 88: 2825–30.PubMedGoogle Scholar
  108. 108.
    Dentice M, Luongo C, Huang S, et al. Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes. Proc Natl Acad Sci U S A 2007, 104: 14466–71.PubMedCentralPubMedGoogle Scholar
  109. 109.
    Kester MH, Toussaint MJ, Punt CA, et al. Large induction of type III deiodinase expression after partial hepatectomy in the regenerating mouse and rat liver. Endocrinology 2009, 150: 540–5.PubMedGoogle Scholar
  110. 110.
    Norman MF, Lavin TN. Antagonism of thyroid hormone action by amiodarone in rat pituitary tumor cells. J Clin Invest 1989, 83: 306–13.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Sogol PB, Hershman JM, Reed AW, Dillmann WH. The effects of amiodarone on serum thyroid hormones and hepatic thyroxine 5′-monodeiodination in rats. Endocrinology 1983, 113: 1464–9.PubMedGoogle Scholar
  112. 112.
    Martino E, Bartalena L, Bogazzi F, Braverman LE. The effects of amiodarone on the thyroid. Endocr Rev 2001, 22: 240–54.PubMedGoogle Scholar
  113. 113.
    Burger A, Dinichert D, Nicod P, Jenny M, Lemarchand-Béraud T, Vallotton MB. Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxin, and thyrotropin. A drug influencing peripheral metabolism of thyroid hormones. J Clin Invest 1976, 58: 255–9.Google Scholar
  114. 114.
    Rosene ML, Wittmann G, Arrojoe Drigo R, Singru PS, Lechan RM, Bianco AC. Inhibition of the type 2 iodothyronine deiodinase underlies the elevated plasma TSH associated with amiodarone treatment. Endocrinology 2010, 151: 5961–70.PubMedCentralPubMedGoogle Scholar
  115. 115.
    Abdulrahman RM, Verloop H, Hoftijzer H, et al. Sorafenib-induced hypothyroidism is associated with increased type 3 deiodination. J Clin Endocrinol Metab 2010, 95: 3758–62.PubMedGoogle Scholar
  116. 116.
    Schoenmakers E, Agostini M, Mitchell C, et al. Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein deficiency disorder in humans. J Clin Invest 2010, 120: 4220–35.PubMedCentralPubMedGoogle Scholar
  117. 117.
    Dumitrescu AM, Liao XH, Abdullah MS, et al. Mutations in SECIS-BP2 result in abnormal thyroid hormone metabolism. Nat Genet 2005, 37: 1247–52.PubMedGoogle Scholar
  118. 118.
    Di Cosmo C, McLellan N, Liao XH, et al. Clinical and molecular characterization of a novel selenocysteine insertion sequence-binding protein 2 (SBP2) gene mutation (R128X). J Clin Endocrinol Metab 2009, 94: 4003–9.PubMedCentralPubMedGoogle Scholar
  119. 119.
    Low SC, Grundner-Culemann E, Harney JW, Berry MJ. SECIS-SBP2 interactions dictate selenocysteine incorporation efficiency and selenoprotein hierarchy. EMBO J 2000, 19: 6882–90.PubMedCentralPubMedGoogle Scholar
  120. 120.
    Dumitrescu AM, Di Cosmo C, Liao XH, Weiss RE, Refetoff S. The syndrome of inherited partial SBP2 deficiency in humans. Antioxid Redox Signal 2010, 12: 905–20.PubMedCentralPubMedGoogle Scholar
  121. 121.
    Dora JM, Machado WE, Rheinheimer J, Crispim D, Maia AL. Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case-control study and meta-analysis. Eur J Endocrinol 2010, 163: 427–34.PubMedGoogle Scholar
  122. 122.
    Maia AL, Hwang SJ, Levy D, Larson MG, Larsen PR, Fox CS. Lack of association between the type 2 deiodinase A/G polymorphism and hypertensive traits: the Framingham Heart Study. Hypertension 2008, 51: e22–3.PubMedCentralPubMedGoogle Scholar
  123. 123.
    Gumieniak O, Perlstein TS, Williams JS, et al. Ala92 type 2 deiodinase allele increases risk for the development of hypertension. Hypertension 2007, 49: 461–6.PubMedGoogle Scholar
  124. 124.
    Grarup N, Andersen MK, Andreasen CH, et al. Studies of the common DIO2 Thr92Ala polymorphism and metabolic phenotypes in 7342 Danish white subjects. J Clin Endocrinol Metab 2007, 92: 363–6.PubMedGoogle Scholar
  125. 125.
    Mentuccia D, Proietti-Pannunzi L, Tanner K, et al. Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the Trp64Arg variant of the beta-3-adrenergic receptor. Diabetes 2002, 51: 880–3.PubMedGoogle Scholar
  126. 126.
    Maia AL, Dupuis J, Manning A, et al. The type 2 deiodinase (DIO2) A/G polymorphism is not associated with glycemic traits: the Framingham Heart Study. Thyroid 2007, 17: 199–202.PubMedGoogle Scholar
  127. 127.
    Dora JM, Machado WE, Rheinheimer J, Crispim D, Maia AL. Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case-control study and meta-analysis. Eur J Endocrinol 163: 427–34.Google Scholar
  128. 128.
    Fiorito M, Torrente I, De Cosmo S, et al. Interaction of DIO2 T92A and PPARgamma2 P12A polymorphisms in the modulation of metabolic syndrome. Obesity (Silver Spring) 2007, 15: 2889–95.Google Scholar
  129. 129.
    Meulenbelt I, Min JL, Bos S, et al. Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis. Hum Mol Genet 2008, 17: 1867–5.PubMedGoogle Scholar
  130. 130.
    Peeters RP, van Toor H, Klootwijk W, et al. Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. J Clin Endocrinol Metab 2003, 88: 2880–8.PubMedGoogle Scholar
  131. 131.
    Butler PW, Smith SM, Linderman JD, et al. The Thr92Ala 5′ type 2 deiodinase gene polymorphism is associated with a delayed triiodothyronine secretion in response to the thyrotropin-releasing hormone-stimulation test: a pharmacogenomic study. Thyroid 2010, 20: 1407–12.PubMedCentralPubMedGoogle Scholar
  132. 132.
    Appelhof BC, Peeters RP, Wiersinga WM, et al. Polymorphisms in type 2 deiodinase are not associated with well-being, neurocognitive functioning, and preference for combined thyroxine/3,5,3′-triiodothyronine therapy. J Clin Endocrinol Metab 2005, 90: 6296–9.PubMedGoogle Scholar
  133. 133.
    Panicker V, Saravanan P, Vaidya B, et al. Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients. J Clin Endocrinol Metab 2009, 94: 1623–9.PubMedGoogle Scholar
  134. 134.
    Meulenbelt I, Bos SD, Chapman K, et al; Translation Research in Europe Applied Technologies for Osteoarthritis (TreatOA). Metaanalyses of genes modulating intracellular T3 bio-availability reveal a possible role for the DIO3 gene in osteoarthritis susceptibility. Ann Rheum Dis 2011, 70: 164–7.PubMedGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2011

Authors and Affiliations

  • A. Marsili
    • 1
  • A. M. Zavacki
    • 1
  • J. W. Harney
    • 1
  • P. R. Larsen
    • 1
  1. 1.Thyroid Section, Division of Endocrinology, Diabetes and HypertensionBrigham and Women’s Hospital, Harvard Institutes of MedicineBoston02115

Personalised recommendations