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Orthogenomics
Published in Kohlstadt Ingrid, Cintron Kenneth, Metabolic Therapies in Orthopedics, Second Edition, 2018
Joseph R. Veltmann, Roberta L. Kline
A gene SNP on DIO2 decreases its enzyme activity (deiodinase 2 ), leading to reduced conversion of T4 to T3 in the peripheral tissues (49). Inadequate T3 levels can lead to poor cartilage metabolism in the joints. Pharmacological therapy (combination T4/T3) was added (50) and important dietary nutrient cofactors (iodine, zinc and selenium) were optimized in her diet to achieve thyroid hormone homeostasis (51).
Biochemistry
Published in Burkhard Madea, Asphyxiation, Suffocation,and Neck Pressure Deaths, 2020
In extrathyroidal tissues, conversion of the pro-hormone T4 to the active form T3 (by iodine atom removal from the outer ring of T4), as well as T3 and T4 metabolism to inactive products (by removal of an inner-ring iodine atom) are mediated by three selenoenzymes called type 1, type 2 and type 3 deiodinase. All deiodinases are membrane-anchored proteins of 29–33 kDa that share substantial sequence homology and catalytic properties, and contain selenocysteine as the key residue within their catalytic centre. Expression levels and activities of type 1 deiodinase (D1 or DIO1, which is preferentially expressed in the thyroid gland, liver and kidney) and type 2 deiodinase (D2 or DIO2) vary among tissues, leading to tissue-specific differences in circulating levels of T3. Type 1 deiodinase catalyzes the removal of inner- or outer-ring iodine atoms in equimolar proportion to generate T3, 3,3′,5′-triiodothyronine (reverse triiodothyronine or rT3) or 3,3′-diiodothyronine (T2), depending on the substrate. Most of the circulating T3 is derived from T4 to T3 conversion by D1 action. Type 2 deiodinase, which is considerably more efficient than D1, catalyzes only outer-ring iodine atom removal from T4, generating the active product T3. D2 is mainly active in the brain, pituitary and skeletal muscle. Type 3 deiodinase (D3 or DIO3) irreversibly inactivates T3, or prevents T4 activation by catalyzing the removal of an inner-ring iodine atom to generate T2 or rT3 respectively. Given these functions, D3 is considered the major physiological inactivator and terminator of thyroid hormone action at the peripheral level [4,6,11,15,47,61,72,76].
Nutritional Regulation of the Growth Plate
Published in Crystal D. Karakochuk, Kyly C. Whitfield, Tim J. Green, Klaus Kraemer, The Biology of the First 1,000 Days, 2017
Thyroid hormones produced by the thyroid gland, namely, 3,5,3′-triiodothyronine (T3) and thyroxine (T4), are important regulators of metabolism. T4 serves as a prohormone, which can be converted to the bioactive T3 by the enzyme type II iodothyronine deiodinase (DIO2) expressed in the thyroid and most other tissues, including the growth plate. Thyroid hormones are an important stimulator of normal linear growth. Hypothyroidism delays longitudinal bone growth and endochondral ossification, while thyrotoxicosis, which results in excessive production of thyroid hormones, accelerates both processes. Nonetheless, both hypothyroidism and thyrotoxicosis eventually lead to short stature. Thyroid hormones support bone growth by promoting the recruitment of resting chondrocyte into a proliferative zone, as well as stimulating chondrocyte hypertrophy [17]. Thyroid hormones are also essential for the normal deposition of the extracellular matrix by stimulating the production of type II and type X collagens and the synthesis of alkaline phosphatase [18]. Thyroid hormones also indirectly stimulate growth by modulating the production of GH and IGF-I. In humans with hypothyroidism and in thyroidectomized mice, both GH and IGF-I levels are decreased, and replacement of GH in hypothyroid rats or thyroid hormone receptor knockout mice partially rescues bone growth [19]. Among the four different isoforms of thyroid hormone receptors (TR-α1, -α2, -β1, -β2, encoded by two genes, THRA and THRB) found in humans, TR-α1 and -α2 are more highly expressed in the growth plate, and therefore appear to elicit much of the effect of thyroid hormone on longitudinal growth. Consistently, the homozygous deletion of THRB showed some delay in skeletal maturation, but exhibited normal growth [20], while homozygous deletion of THRA has not yet been described. So far, most cases of thyroid hormone resistance found in humans that showed postnatal growth retardation is caused by a dominant negative mutation of either TR-α or TR-β receptors [21]. Studies in humans showed that malnutrition decreases both T3 and T4 levels, and thereby slows linear growth [22]. Similarly, iodine deficiency, which is very common in some developing countries, leads to thyroid hormone deficiency and decreased linear growth. In several animal models, however, it was shown that food restriction mostly reduces T3 levels rather than T4 [23], suggesting that malnutrition may affect the conversion of T4 to T3 rather than thyroid hormone production.
Effect of sodium selenite on synaptic plasticity and neurogenesis impaired by hypothyroidism
Published in International Journal of Neuroscience, 2022
Ercan Babur, Özlem Canöz, Burak Tan, Cem Süer, Nurcan Dursun
Ptu is a thiourea derivative drug used in the treatment of hyperthyroidism. Its effect is shown by inhibition of thyroid peroxidase and 5-deiodinase and DIT-MIT binding. In our study, when free T4 levels were compared between groups, a statistically significant decrease was observed in the Ptu group compared to the control group. Se treatment did not affect fT4 thyroid hormone levels although fT3 levels increased by %60 in the Se treated rats. Chaonoine, et al demonstrated after short term thyroidectomy, serum T4 concentrations fell in both the Se-supplemented and Se-deficient rats [29]. Also, altered Se intake had no effect on the fall of serum T3. Esposito and colleagues showed that Se treatment for Hashimoto patients increased fT3 levels while decreasing fT4 levels. This effect of Se supplementation seems to be due to the increase of DIO 1 enzyme activity catalyzing the conversion of T4, T3 rather than the effect of selenium on thyroid hormone synthesis. Type 2 deiodinase enzyme is an important factor in adapting to changes in thyroid hormone levels in the central nervous system. When the thyroid hormone level decreases, such as hypothyroidism, DIO2 enzyme activity increases and attempts to maintenance thyroid hormone levels in the brain cells.
Triiodothyronine alongside levothyroxine in the management of hypothyroidism?
Published in Current Medical Research and Opinion, 2021
Ulrike Gottwald-Hostalek, George J. Kahaly
Up to about four-fifths of thyroid hormone secretion is in the form of T4, which is chemically identical to administered LT4, with T3 accounting for almost all of the remainder2. The kinetics of thyroid hormones vary by thyroid status and the terminal elimination half-life in hypothyroid subjects has been described as 7.5 days for T4 and 1.4 days for T34,5. T3 is the active thyroid hormone in the periphery1,2. T4 (endogenous or via LT4 treatment) and T3 enter cells via a membrane transporter, following which T4 is converted to T3 by intracellular deiodinases mainly in the liver, especially by Deiodinase 2 (DIO2); these enzymes can also deactivate thyroid hormones2,6,7. Furthermore, these enzymes may provide another layer of regulation of thyroid homeostasis, at the tissue level8. Intracellular T3 then binds to one of several thyroid hormone receptors and translocates to the nucleus, where it exerts its biological actions by altering the transcription of numerous genes in target organs, including the brain, liver, muscle, heart and circulation, pancreas, bone, and fat, among others9,10.
Seasonal variations in levels of human thyroid-stimulating hormone and thyroid hormones: a meta-analysis
Published in Chronobiology International, 2021
N. V. Kuzmenko, V. A. Tsyrlin, M. G. Pliss, M. M. Galagudza
T4 has minimal physiological activity and can be further transformed by deiodinases DIO1 and DIO2 to active triiodothyronine (T3) and by DIO3 to inactive reverse triiodothyronine (rT3) (Arrojo et al. 2011; Dardente et al. 2014, 2010). Changes in DIO2 and DIO3 activity in tissues combined with the seasonal dynamics of TSH expression regulate the circannual-associated changes in metabolism and reproductive behavior of mammals (Arrojo et al. 2011; Dardente et al. 2014; Nakane and Yoshimura 2014). TSH stimulates DIO2 expression by binding to corresponding receptors in ependymal cells of the mediobasal hypothalamus (Dardente et al. 2014). For most mammalian species studied to date, a typical expression pattern of DIO isoforms is characteristic with high expression levels of DIO2 and low expression of DIO3 occurring during long days of sunlight and high expression levels of DIO3 and low expression of DIO2 occurring during short days of sunlight (Ebling 2014).