Invest in ME Conference 12: First Class in Every Way
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Deiodinase type 1 Polymorphism and Low T3 Syndrome

Discussion in 'Other Health News and Research' started by pattismith, Mar 3, 2018.

  1. pattismith

    pattismith Senior Member

    Deiodinase Type 1 (D1) is involved in recycling rT3, and any impairment of it's activity can be a factor for Low T3 syndrome.
    Women have lower D1 activity and may be more sensitive to the Low T3 than men.

    Common polymorphism in DIO1 gene is involved in D1 activity:

    • Among patients, the _minor_ allele of rs11206244 was associated with reduced fT3:fT4 ratio from 0.193 in Common homozygous to 0.175 in Minor homozygous (-0.18) p for trend = 0.004).

    • Among patients, the _major_ allele of rs2235544 was associated with reduced fT3:fT4 ratio (from 0.196 in Minor homozygous to 0.177 in Common homozygous (-.019), p for trend = 0.01).

    Thyroid Hormons metabolism:

    "D1 and D2 have outer ring deiodinase activity, converting the prohormone T4 to its bioactive form T3 and degrading rT3 to 3,3’-T2

    D3 mediates the degradation of thyroid hormone since it has only IRD activity. The brain is the predominant D3-expressing tissue in adult animals, and may thus be the main site for the clearance of plasma T3 and for the production of plasma rT3

    In iodine deficiency, D1-mediated peripheral T3 production decreases but this is in part compensated by an increased thyroidal T3 production, which is mediated by an increased TSH secretion as well as by increased efficiency of D2-mediated T3 production. Simultaneously, neuronal D3 expression decreases thereby prolonging the local half-life of T3.

    In non-thyroidal illness (NTI) plasma T3 is often decreased and plasma rT3 increased; plasma FT4 is still in the normal range depending on the severity of disease. The changes in plasma T3 and rT3 are explained by a diminished conversion of T4 to T3 and of rT3 to 3,3-T2 by D1 in the liver. Although this may be caused to some extent by decreased D1 expression or cofactor levels, a diminished activity of transporter(s) mediating hepatic uptake of T4 and rT3 appears to be another important mechanism. This also holds for the generation of the low T3 syndrome in malnutrition.

    In addition to a decreased peripheral T3 production, the low T3 syndrome of NTI may also be caused by stimulated thyroid hormone degradation due to induction of D3 in different tissues. Pathological expression of D3 may be so high that this results in a state of consumptive hypothyroidism with low serum (F)T4 and T3 and very high rT3 levels. This has been shown in different patients with hemangiomas which express very high D3 activities."
  2. pattismith

    pattismith Senior Member

    I am heterozygous for the 2 snp quoted above, so my D1 has not an optimal efficiency...
    BadBadBear likes this.
  3. pattismith

    pattismith Senior Member

    According to this site

    "Type 1 deiodinase – D1

    In humans, the D1 enzyme has a much higher substrate preference for rT3 than for T4 [2], suggesting that its main function is to deiodinate rT3 to form T2, both conserving iodine and clearing rT3. In conditions in which D1 is downregulated, an increase in circulating rT3 is seen because the conversion of rT3 to T2 is significantly reduced, resulting in an accumulation of rT3.

    D1 is downregulated by selenium deficiency and in the non-thyroidal illness syndrome, as well as some cancers.
    It is also inhibited by some drugs, notably amiodarone, propranolol, propylthiouracil, dexamethasone, and ipodate.
    On the other hand, D1 is upregulated by T3, which restores the clearance of rT3 (via conversion to T2) and reduces the levels of circulating rT3 relative to T3. T3 therapy has therefore been used in some studies of critically ill patients in an attempt to restore intracellular thyroid function by upregulating the D1 deiodinase, but in general such treatment has not affected prognosis and it remains controversial. Most studies find that successful treatment of the underlying illness, as well as maintaining nutritional support and re-introducing mobility as soon as possible, naturally restores the T3/rT3 ratio to normal."

    I looked I the study quoted in the previous article:

    "Regulation of type 1 iodothyronine deiodinase expression

    The expression and activity of D1 are modulated by a variety of hormonal, nutritional, and developmental factors, the most potent being thyroid hormone ( Harris et al . 1978 , Kaplan & Utiger 1978 , Maia et al . 1995 b , Koenig 2005 ).

    The T3 effect in rat and mouse Dio1 gene is due to transcriptional activation and does not require protein synthesis ( Berry et al . 1990 , Maia et al . 1995 c ).

    T3 also positively regulates the human DIO1 gene at the transcriptional levels by interaction with two complex TREs located in the promoter region ( Toyoda et al . 1995 , Jakobs et al . 1997 b , Zhang et al . 1998 ).

    In addition, the human DIO1 promoter contains thyroid hormone response- retinoic acid (RA) response elements that mediate thyroid hormone receptor (TR) b activation ( Schreck et al . 1994 , Toyoda et al . 1995 ).

    Interestingly, a recent report indicates that, in mice, the promoter of the Dio1 gene is also regulated by the hepatocyte nuclear factor 4 a (HNF4 a ; Ohguchi et al . 2008 ). Based on the findings of that study, HNF4 a would play a role in thyroid hormone homeostasis by cooperatively regulating the 5 0 -deiodination of T 4 with GATA4 and T3 -inducible Kruppel-like transcription factor 9 (KLF9).

    The authors also suggest that the T3 regulation of Dio1 gene is probably due to an indirect mechanism that involves the T3 -dependent stimulation of KLF9 expression ( Ohguchi et al . 2008 ).

    In addition to thyroid hormones, other physiological compounds modulate D1 expression ( Ta b l e 1 ). The administration of GH to euthyroid adults is known to increase the ratio of plasma T3 to T4 whereas reducing that of rT3 to T4 ( Jorgensen et al . 1989 , Alcantara et al . 2006 ), in a peripheral mechanism that probably involves augmented D1 and/or a reduction in D3 activity ( Darras et al . 1992 , Van der Geyten et al . 1999 ).

    TSH also induces D1 synthesis in the human thyroid gland, by a mechanism that involves the T3 -dependent stimulation of KLF9 expression ( Ohguchi et al . 2008 ). In addition to thyroid hormones, other physiological compounds modulate D1 expression ( Ta b l e 1 ). The administration of GH to euthyroid adults is known to increase the ratio of plasma T3 to T4 whereas reducing that of rT3 to T4 ( Jorgensen et al . 1989 , Alcantara et al . 2006 ), in a peripheral mechanism that probably involves augmented D1 and/or a reduction in D3 activity ( Darras et al . 1992 , Van der Geyten et al . 1999 ). TSH also induces D1 synthesis in the human thyroid gland, by a mechanism that involves, at least in part, the second messenger cAMP, via a protein synthesis- dependent process ( Ishii et al . 1983 , Pekary et al . 1994 , Beech et al . 1995 ).

    Although the mechanism for the stimulation of Dio1 transcription by cAMP has not been fully elucidated, its effects are additive to that of T3 , resulting in a fivefold stimulation relative to control ( Mori et al . 1996 ). Data on the effects of glucocorticoids on D1 expression are controversial.

    Although some in vitro studies have shown that glucocorticoids induce D1 mRNA and activity in rat liver, others described no changes in D1 activity ( Menjo et al . 1993 , Van der Geyten et al . 2005 ).

    Studies using rat liver and kidney cell cultures observed an increase of D1 mRNA and activity after incubation with dexamethasone ( Davies et al . 1996 b ). Controversially, studies on a pituitary rat cell line found that dexamethasone alone had no effect on Dio1 gene expression but did enhance the effect of T3 ( Maia et al . 1995 b ).

    On the other hand, the administration of dexamethasone to euthyroid adult males increased the circulating rT and rT3 /T4 ratios, which could be a result of the augmented production of rT3 instead of decreased clearance ( LoPresti et al . 1989 ).

    Deiodinases are selenoproteins and, thus, susceptible to selenium deficiency. The effect of selenium deficiency on the synthesis of intracellular selenoproteins is apparently tissue dependent, being more pronounced in liver, skeletal muscle, and heart ( Meinhold et al . 1992 , Bermano et al . 1995 , Bates et al . 2000 ). In rats, selenium deficiency decreases D1 activity in liver and kidney by a mechanism that involves protein translation, secondary to a blockage in the Sec incorporation ( Beckett et al . 1987 , DePalo et al . 1994 ).

    The administration of T3 did not affect D1 activity in the selenium-deficient rats, whereas selenium-fed controls had a twofold increase in enzyme activity.

    Mice with excessive iodine intake presented a decreased selenium concentration in urine and liver and reduced renal and hepatic D1 mRNA and activity levels ( Yang et al . 2006 ). The selenium supplementation corrected these alterations.

    In humans, selenium deficiency is observed in subjects receiving diets with restricted protein content, such as those given for phenylketonuria, and also in elderly patients ( Kauf et al . 1994 , Calomme et al . 1995 , Lombeck et al . 1996 , Jochum et al . 1997 ).
    Seleno-deficient individuals have mildly elevated serum T4 and T4 to T3 ratios, but normal TSH.
    Indeed, the deficiency of this essential micronutrient has been implicated in the pathogenesis of myxedematous endemic cretinism, prevalent in African endemic goiters, and associated to a thyroid ‘exhaustion’ atrophy occurring near birth. This might result from the low resistance of a fragile tissue to enhanced H 2 O 2 generation under intense thyroid stimulation by high TSH levels ( Goyens et al . 1987 , Vanderpas et al . 1990 , Duntas 2010 ). Of note, deterioration of thyroid function was observed after selenium administration to iodine-deficient people in an African region of endemic goiter, suggesting that the reduction in D1 activity during selenium deficiency can protect against iodine deficiency, presumably by reducing the deiodination of T4 ,T3 ,orT3 S"
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  4. pattismith

    pattismith Senior Member

    The relationship of 19 functional polymorphisms in iodothyronine deiodinase and psychological well-being in hypothyroid patients

    Levothyroxine supplementation is insufficient for the management of one tenth of patients with hypothyroidism. Iodothyronine deiodinases have been suggested to play a role in residual hypothyroid symptoms of these patients by controlling local thyroid hormone homeostasis. Previous research has suggested a relationship between commonly inherited variations in type 2 iodothyronine deiodinase and impaired well-being. We evaluated the prevalence of iodothyronine deiodinase genotypes and their association with psychological well-being in the Korean hypothyroid population.

    A prospective observational study. We enrolled 196 hypothyroid subjects (136 chronic autoimmune thyroiditis and 60 thyroid cancer) and assessed baseline well-being using six validated questionnaires. Genotyping was conducted for 19 single nucleotide polymorphisms in type 1, 2, and 3 iodothyronine deiodinase using Sequenom MassARRAY matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in all patients.

    Frequencies of iodothyronine deiodinase genotypes and well-being scores were not different in hypothyroid subjects according to their disease types.

    Minor genotypes of a few iodothyronine deiodinase 1 variants (rs11206244, rs2294512, and rs4926616) were associated with reduced psychological well-being.

    However, iodothyronine deiodinase 2 and 3 variants had no effect on baseline well-being.

    Minor variations in iodothyronine deiodinase 1 were associated with decreased well-being in the Korean hypothyroid population, whereas iodothyronine deiodinase 2 and 3 were not.

    Due to controversial results among different ethnicities, further studies to clarify the effects of iodothyronine deiodinase polymorphisms on psychological well-being are warranted in hypothyroid individuals.
    sb4 likes this.
  5. pattismith

    pattismith Senior Member

    Inhibition of thyroid type 1 deiodinase activity by flavonoids.
    Some dietary flavonoids inhibit thyroperoxidase and hepatic deiodinase activity, indicating that these compounds could be classified as anti-thyroid agents. In this study, we evaluated the in vitro effect of various flavonoids on thyroid type 1 iodothyronine deiodinase activity (D1). D1 activity was measured in murine thyroid microsome fractions by the release of 125I from 125I-reverse T3. D1 activity was significantly inhibited by all the flavonoids tested; however, the inhibitory potencies on thyroid D1 activity differed greatly among them.
    A 50% inhibition of D1 activity (IC(50)) was obtained at 11 microM baicalein, 13 microM quercetin, 17 microM catechin, 55 microM morin, 68 microM rutin, 70 microM fisetin, 72 microM kaempferol and 77 microM biochanin A.
    Our data reinforce the concept that dietary flavonoids might behave as antithyroid agents, and possibly their chronic consumption could alter thyroid function.
    sb4 likes this.
  6. Gondwanaland

    Gondwanaland Senior Member

    I am -/- for both SNPs, but I have issues with Sulfation and Glucuronidation. Taking Carcinine resolved this issues, but I wasn't able to cope with the speedy hormone breakdown it caused at even very low doses (I am already very thin to take supplements that speed metabolism up).
    Interestingly I craved foods high in flavonoids while taking Carcinine, which otherwise I avoid.

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