How the three deiodinases regulate T3

Dear thyroid patients: If you’ve never heard about the deiodinases, your life and future health may depend on you learning about them.

The deiodinases can either work with your thyroid meds or against them.

It’s a lifelong condition, being on thyroid therapy, so there’s time for thyroid knowledge to sink in. I don’t have a bioscience degree and I eventually got this.  I’ll try to make it as simple as possible. Try not to be intimidated if it’s new to you. There are only some new words and concepts to learn, and learning them will help you defend your T3 hormone and your health.

Let’s get started.

First of all, what is a “Deiodinase”?

A deiodinase is an enzyme that converts thyroid hormones from one form to another.

“Iodine” is at the root of the word “Deiodinase.”

This is because It performs its action by removing one iodine atom from the hormone molecule.

Therefore, a deiodinase “De – IODINE – ates” the hormone molecules, enabling them to change their structure and function as thyroid hormone.

The thyroid hormone begins its life as either T4 or T3.

Yes, you read that correctly.  Most doctors don’t know this yet, that T4 is not the only source of T3 in the human body. A recent article has proven a revolutionary fact: Some T3 is created “de novo” (it’s born as T3) within the thyroid gland, and TSH preferentially drives up T3 synthesis more than T4 (Citterio et al, 2017, 2018, 2019 — see our review of their 2017 article).

When T4 is converted into a form of T3, then T3 becomes one of two types of T2, and finally, T1. (Chatzitomaris et al, 2017)

Alternatively, T4 can be converted into Reverse T3, which then gets converted into the other type of T2, etc.

(There are also other minor metabolites of thyroid hormone created by the body, but I won’t get into those right now. As this process occurs in thyroid hormone metabolism [activation, transformation] and catabolism [breakdown], we call the byproducts “thyroid hormone metabolites.”)

The deiodinases’ activity upon thyroid hormones are an important part of the body’s method of circulating iodine.

To generate the right amount of thyroid hormone, the human body requires just the right amount of iodine (not too much, not too little). (Dayan & Panicker, 2009)

The most important hormone in this cycle is T3, since it is the only hormone known to trigger a huge series of “genomic” activities within the thyroid hormone receptor located in every cell throughout our body.

That means it turns on and off genes that are just waiting to be activated by T3.

When the receptor does not have T3 bound to it, the gene it’s attached to is either in an ON state or an OFF state. When the receptor has T3, it’s a toggle, like a light switch, turning it to the opposite state, either turning the light off, or turning it on.

Sorry, but T4 can’t do this.

Without T3, our body cannot make energy from mitochondria.

The T3 hormone does more than just drive our metabolic rate (body temperature and heart rate). It turns off and on different genes in each different organ and tissue. Without the perfect amount of T3, not too much and not too little, our cells, organs and tissues, yes–even our brain–cannot function properly.

Unfortunately what doctors don’t seem to understand is that TOO LITTLE T3 is just as dangerous as too much, and when we lack it, and we can’t make enough of it out of T4 (and many on T4 meds cannot), we truly need it from T3-based medication.

Deiodinase type 1 (D1)

• The DIO1 gene is responsible for creating the Deiodinase type 1 enzyme.
• Deiodinase type 1 converts T4 to T3 primarily in the bloodstream through organs that quickly exchange plasma — DOI1 genes are highly expressed in thyroid, liver, and kidney tissues. The availability of T3 in blood plasma and serum is vital for organs that depend on T3 from this source. T3 in blood is especially important for the cardiovascular system — both the blood vessels and the heart muscle itself are activated by T3 and T3 alone, and they are very sensitive to both excess and deficiency.
• The bloodstream is the “entry point” for thyroid hormones to flow into the rest of the body. If you are a bit low in T3 in blood, you may have a further deficit depending on your Deiodinase type 2.

Deiodinase type 2 (D2)

• The DIO2 gene is responsible for producing the Deiodinase type 2 enzyme.
• Deiodinase type 2 is also expressed in significant levels in the thyroid gland, making the thyroid a major contributor to conversion. D2 is also the primary driver of converting T4 to T3 in tissues that exchange less T4 & T3 with bloodstream supply.
• According to Arrojo e Drigo and Bianco, 2011, D2 enzyme is “responsible for 70 % of all extrathyroidal T3 production in healthy humans.” Some of the T3 produced in cells by this enzyme exits the cells and is added to plasma in the bloodstream once again.
• The TSH hormone, both within the thyroid gland and in peripheral tissues, plays a role in upregulating Deiodinase type 2 to convert T4 to T3 in just the right amounts needed, both within bloodstream, and within cells in all organs and tissues.
• T4 hormone, when too abundant, deactivates Deiodinase 2. Therefore, D2 is not only an essential enzyme but one that is vulnerable within the context of T4 therapy.

Deiodinase type 3 (D3)

• Deiodinase type 3 is a lot more complex.
• It reverses the process of hormone conversion by slowing down D2 and D1.
• It converts T4 to Reverse T3 and converts T3 into T2, and it does this in both the bloodstream and peripheral tissues at the same time.
• Learn about its function, activity, and measurement in a separate blog post:
  • Deiodinase type 3 and Reverse T3

REFERENCES

Thyroid hormone conversion (and inactivation)

Arrojo e Drigo, R., & Bianco, A. C. (2011). Type 2 deiodinase at the crossroads of thyroid hormone action. The International Journal of Biochemistry & Cell Biology, 43(10), 1432–1441. https://doi.org/10.1016/j.biocel.2011.05.016

Charalambous, M., & Hernandez, A. (2013). Genomic imprinting of the type 3 thyroid hormone deiodinase gene: Regulation and developmental implications. Biochimica et Biophysica Acta, 1830(7), 3946–3955. https://doi.org/10.1016/j.bbagen.2012.03.015

Chatzitomaris, A., Hoermann, R., Midgley, J. E., Hering, S., Urban, A., Dietrich, B., … Dietrich, J. W. (2017). Thyroid Allostasis–Adaptive Responses of Thyrotropic Feedback Control to Conditions of Strain, Stress, and Developmental Programming. Frontiers in Endocrinology, 8. https://doi.org/10.3389/fendo.2017.00163

Larsen, P. R., & Zavacki, A. M. (2012). Role of the Iodothyronine Deiodinases in the Physiology and Pathophysiology of Thyroid Hormone Action. European Thyroid Journal, 1(4), 232–242. https://doi.org/10.1159/000343922

Sabatino, L., Lubrano, V., Balzan, S., & Kusmic, C. (2015). Thyroid hormone deiodinases D1, D2, and D3 are expressed in human endothelial dermal microvascular line: Effects of thyroid hormones. Molecular and Cellular Biochemistry, 399(1–2), 87–94. https://doi.org/10.1007/s11010-014-2235-8

Taylor, P. N., Peeters, R., & Dayan, C. M. (2015). Genetic abnormalities in thyroid hormone deiodinases: Current Opinion in Endocrinology & Diabetes and Obesity, 22(5), 402–406. https://doi.org/10.1097/MED.0000000000000180

Too, H. C., Shibata, M., Yayota, M., & Iwasawa, A. (2017). Iodothyronine deiodinases: key enzymes behind the action of thyroid hormone. Reviews in Agricultural Science, 5(0), 45-55–55. https://doi.org/10.7831/ras.5.44-55

The direct synthesis of T3 hormone in the thyroid gland, and higher % of T3 synthesis when it is stimulated by more TSH

Citterio, C. E., Veluswamy, B., Morgan, S. J., Galton, V. A., Banga, J. P., Atkins, S., … Arvan, P. (2017). De novo triiodothyronine formation from thyrocytes activated by thyroid-stimulating hormone. The Journal of Biological Chemistry, 292(37), 15434–15444. https://doi.org/10.1074/jbc.M117.784447

Citterio, C. E., Morishita, Y., Dakka, N., Veluswamy, B., & Arvan, P. (2018). Relationship between the dimerization of thyroglobulin and its ability to form triiodothyronine. The Journal of Biological Chemistry, 293(13), 4860–4869. https://doi.org/10.1074/jbc.RA118.001786

Citterio, C. E., Targovnik, H. M., & Arvan, P. (2019). The role of thyroglobulin in thyroid hormonogenesis. Nature Reviews. Endocrinology, 15(6), 323–338. https://doi.org/10.1038/s41574-019-0184-8

Iodine and its impact on T3 – T4 synthesis and thyroid hormone levels in blood

Dayan, C. M., & Panicker, V. (2009). Interpretation of Thyroid Function Tests and Their Relationship to Iodine Nutrition-Chapter 5:Changes in TSH, Free T4, and Free T3 Resulting from Iodine Deficiency and Iodine Excess. In Comprehensive Handbook of Iodine (pp. 47–54). Elsevier Inc.