2017 study of T2 hormones, blood glucose and other metabolic markers

Study T3 and T4

Do you know about the effects of the two kinds of T2 thyroid hormone that your body produces?

A significant 2017 mouse study examined treatment with T3 as well as two types of T2 hormone.

One type of T2 is produced by removing iodine from the outer ring of the T3 molecule.

The other type of T2 is formed by inner-ring deiodination of either T3 or Reverse T3. You can think of this derivative as “Reverse T2.”

Guess what? The active T2 is generally benign, but Reverse T2 can be harmful in certain concentrations and is more common during illness.

What is driving this research?

A subfield of thyroid science has been investigating “thyroid hormone analogs” and “metabolites” to discover whether targeted therapies could be developed based on treating people with them instead of with T3 or T4 medications.

One motivation that drives this research on metabolites is the desire for the known positive effects of thyroid hormone therapy (especially T3 therapy) together with the fear of the adverse effects of excess T3 hormone on the body.

As the researchers of this study explain in their conclusion,

The stated goal of selective modulation of TH [Thyroid Hormone]-signalling pathways is to selectively induce potentially desirable aspects of TH excess states, such as reduced cholesterol and fat loss, separated from other thyrotoxic effects.

The study

  • da Silva Teixeira, S., Filgueira, C., Sieglaff, D. H., Benod, C., Villagomez, R., Minze, L. J., … Nunes, M. T. (2017). 3,5-diiodothyronine (3,5-T2) reduces blood glucose independently of insulin sensitization in obese mice. Acta Physiologica (Oxford, England), 220(2), 238–250.
  • Link to abstract: https://onlinelibrary.wiley.com/doi/pdf/10.1111/apha.12821

Why the study is significant for thyroid patients

Thyroid patients take hormone medications that directly influence their levels of T4, T3, and Reverse T3.

By influencing these major hormones, their therapy can also influence their levels of T2 hormones produced “downstream” from them.

Thyroid patients can struggle with weight gain — specifically, excess fat. In this research, factors that contribute to weight gain were studied in relation to T3 and the two types of T2.  It is well known that T3 raises metabolic rate and body temperature, and therefore energy expenditure. T3 also improves metabolism of lipids (fats).

The researchers were looking for effects related to Type 2 Diabetes, in which high blood glucose results from impaired insulin and glucose in skeletal muscle and liver.  Therefore, they examined biomarkers related to Type 2 Diabetes.

Even without a diabetes diagnosis, thyroid patients may have difficulty with insulin sensitivity and low or high blood glucose levels because the T3 hormone plays an important role in regulating blood glucose and insulin response.

Can the two forms of T2 do the same things as T3 without causing thyrotoxicosis? That’s the question.

They did a study on mice rather than humans because a mouse study can measure these hormones’ effects on muscle, fat tissue, and liver at the cellular level. This helps us understand their potential biological effects before we treat humans with them.

They put the mice on a high fat diet to see more clearly the potential effects of these metabolites on their weight loss.

Overall results

The study found that the good T2 helped with fat, insulin and glucose metabolism.

In contrast, the bad “Reverse T2” worsened metabolic health.

The two types of T2

Thyroid hormone conversion occurs as part of the natural process of circulating iodine molecules in the body.

The T4 hormone becomes T3 as the body removes one of its iodine atoms (“de-iodination”).  Three deiodinase enzymes are responsible for breaking down T4 into various forms of T3, T2, and T1.

Deiodinase Type 1 (D1) and Type 2 (D2) convert T4 into the “active” thyroid hormone T3. This happens within our bloodstream and peripheral tissues.

If a different iodine atom is removed from T4, it becomes Reverse T3.

Every day, a healthy human body naturally produces some Reverse T3 as well as T3.

However, there are two very different types of T2 hormones:

  • 3,5 – T2 is the product of T3 conversion into T2, when it is converted by Deiodinase Type 1 and Type 3.
  • 3,3′ – T2 is the product mainly of Reverse T3 conversion into a different kind of T2, when converted by Deiodinase Type 3.
    (NOTE: Likely only a small amount of this T2 comes from deiodination of T3 hormone [See Chopra, 1977], and when RT3 is dominant in serum, T3 is usually depressed.)

In Wikipedia you can see that 3,5-T2 has a different molecular structure from 3,3′-T2.

The study showed that these two forms of T2 also have different metabolic effects.

Both T3 and its metabolite 3,5-T2

Metabolic effects

  • Chronic treatment with T3 and 3,5-T2 decreased body weight and increased body temperature in the face of increased food intake and these effects were paralleled by decreases in blood glucose.” This agreed with previous studies in which it was shown that “high doses of 3,5-T2 enhance metabolic rate and reduce blood glucose in rodents (Baltaci et al. 2004, Lehmphul et al. 2014)”
  • 3,5-T2 correlated with reduced liver levels of GLUT2 and reduced glucose output from liver. (Diabetic animals have more GLUT2, which may contribute to high blood glucose.)
  • However,
    • 3,5-T2 did not alter insulin sensitivity.
    • 3,5-T2 also did not change glucose transporters in muscle or white fat.
    • T3 improved responses in the glucose tolerance test, whereas 3,5-T2 did not, raising the possibility that these hormone derivatives may not act in exactly the same way.” 
  • Therefore, 3,5-T2 cannot replace T3. They share some functions, but not others.

Affinity to thyroid hormone receptors (TRs)

  • “We confirmed that 3,5-T2 weakly activates TRs at very high doses (Mendoza et al. 2013).” 
  • This is significant, since many have been incorrectly taught that only T3 hormone can activate TRs.
  • However, “Pharmacologic doses of 3,5-T2 are required for desirable effects,” because “natural circulating 3,5-T2 levels” are usually “far below levels required to activate TRs in cultured cells.”
  • 3,5-T2 can also have “non-genomic” effects — effects that do not require it to bind to TRs and influence genetic expression. Non-genomic effects often occur at the cell membrane and in the cytosol, rather than in the cell nucleus.

Effect on TSH and heart weight

  • “3,5-T2 increased heart weight,” a sign of hyperthyroidism. This was likely due to the pharmacologic doses of T2 required to have a significant effect in the study.
  • 3,5-T2 “suppressed the H-P-T axis, as judged by reduced TSH levels.” However, “3,5-T2 did not suppress TSH as strongly as T3″

3,3′-T2, the product of Reverse T3 conversion

Metabolic effects

  • “mice subjected to 3,3′-T2 treatment did not lose weight and, in fact, displayed a trend to increased body weight and adiposity [excess body fat] accompanied by
    • increased food intake,
    • increased liver fat,
    • reduced glucose tolerance and
    • increased serum insulin.”
  • 3,3′-T2 also stimulated feeding response”
  • Thus, … 3,3′-T2 worsens metabolic parameters in HFD mice.”

Affinity to thyroid hormone receptors (TRs)

  • 3,3′-T2 acts as a more effective and potent TR agonist that binds TRs with higher affinity [than 3,5’T2]”‘
  • Therefore, Reverse T3’s metabolite competes with T3’s metabolite. Reverse T3’s metabolite is more likely to win in the odds of binding to a thyroid hormone receptor. 

Effect on TSH and heart weight

  • While 3,3′-T2 did not affect heart weight, it did suppress TSH.”

Our commentary

Health implications

Although mice are not humans, and we need to study T2 in humans, we could see some potential health implications:

  • Healthy, normal levels of T3 hormone, in the presence of normal levels of T4 and its byproduct Reverse T3, bring about good metabolic health partly due to the positive effects of the natural breakdown of T3 into 3,5-T2 and because 3,3’T2 is not ecxcessive.
  • If you have higher levels of T3 hormone, you will also have higher levels of 3,5-T2 that will lead to weight loss and fat loss, due to the combined effects of T3 and 3,5-T2.
  • In contrast, if T4 and its “inactive” byproduct Reverse T3 become excessive and T3 hormone is depleted, you will likely suffer in metabolic health partly as a result of the effects of excess levels of Reverse T3’s metabolite 3,3′-T2, which also competes with 3,5-T2 for thyroid hormone receptors.

In addition, the study gives insight into the potential “oral dosing effects” of T3 medication on TSH:

  • The TSH-suppressing effects of 3,5-T2 may explain why oral doses of T3 hormone have a more powerful TSH-suppressive effect than T4 oral doses do.  Within the first few hours of ingestion, some of the T3 hormone breaks down immediately into T2, and both T3 and T2 together may suppress TSH more strongly.

Finally, the study may give insight into TSH in Low T3 syndrome / nonthyroidal illness:

  • In critical illness, when the body inactivates T4 and T3, both types of T2 are increased in bloodstream.  Reverse T3 rises significantly in this state.
  • At the same time, Reverse T3 is not broken down as quickly during critical illness, and T3 levels are low because T3 is being converted into T2.
  • While 3,5-T2 is usually elevated in this state, 3,3′-T2 levels vary and are high in only certain types of illness (see Pinna, 1998).
  • As concentrations of either type of T2 metabolites rise, they will produce mild TSH suppression.
  • This is likely why the low T3 hypothyroid state is not accompanied by high TSH.

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