How thyroid hormones work in cells.: This is (so... - Thyroid UK

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How thyroid hormones work in cells.

diogenes profile image
28 Replies

This is (so far in preprint form so not generally available) a paper which shows how our cells are controlled by deiodinase enzymes. The answer is quite clear: The deiodinase called D2 is stimulated by T3 using one activator, whereas deiodinase D3 is inhibited by T3 using a deactivator. The latter is the one that makes rT3 from T4. So the expression of the right amount of T3 in each cell depends on the balance between D2 and D3 action, which pull opposite ways. This accounts not only for the unique expression in a particular tissue or organ, but the balance between each action can vary from moment to moment according to individual tissue need. So the way individual tissues respond to T4 (competing T3 or rT3 production) explains completely how individual tissues and organs act both in the long term and the short.

A very important paper. I don't know the journal yet as it was sent to me by certain channels . When it is finally accepted I'll send on to TUK or show the doi number if possible to download free


Samuel C. Russo , Federico Salas-Lucia , and Antonio C. Bianco

28 Replies
jimh111 profile image

It's in this journal but behind a paywall.

Have you got your introductory comments the wrong way around? Should it say D2 is inhibited by T3 and D3 is stimulated by T3?

A further mechanism that is often ignored is that TSH stimulates D2. So if the axis is down-regulated, or TSH has low bioactivity, there is reduced D2 and hence hypothyroidism is D2 expresssing tissues - even if serum fT3 is normal or rendered normal by tablets.

diogenes profile image
diogenes in reply to jimh111

I think I got it right: D2 enhances activity for T3 p production according to need for extra energy, whereas D3 slows things down and rT3 is preferentially made instead This is the actual abstract:


Deiodinases modify the biological activity of thyroid hormone (TH) molecules, i.e. they may activate thyroxine (T4) to 3,5,3’-tri-iodothyronine (T3), or inactivate T3 to 3,3’diiodo-L-thyronine (T2) or T4 to reverse tri-iodothyronine (rT3). Although evidence of deiodination of T4 to T3 was available since the 1950s, objective evidence of TH metabolism was not established until the 1970s. The modern paradigm considers that the deiodinases not only play a role in the homeostasis of circulating T3, but they also provide dynamic control of TH signaling: cells that express the activating type 2 deiodinase (D2) have enhanced TH signaling due to intracellular build-up of T3; the opposite is seen in cells that express type 3 deiodinase (D3), the inactivating deiodinase. D2 and D3 are expressed in metabolically relevant tissues such as brown adipose tissue, skeletal muscle and liver, and their roles have been investigated using cell, animal, and human models. During development, D2 and D3 expression customize for each tissue/organ the timing and intensity of TH signaling. In adult cells, D2 is induced by cyclic adenosine monophosphate (cAMP) and its expression is invariably associated with enhanced T3 signaling, expression of PGC1 and accelerated energy expenditure. In contrast, D3 expression is induced by hypoxia-inducible factor 1- α (HIF-1a), dampening T3 signaling and the metabolic rate. The coordinated expression of these enzymes adjusts TH signaling on a time- and tissue-specific fashion, affecting metabolic pathways in health and disease states.

jimh111 profile image
jimh111 in reply to diogenes

I was thinking of this sentence "The deiodinase called D2 is stimulated by T3 using one activator, whereas deiodinase D3 is inhibited by T3 using a deactivator. ". I don't know about the activator / deactivator until we see the paper but it seems to say T3 promotes D2 and inhibits D3 whereas T3 promotes D3 and inhibits D2 thus helping to maintain steady intracellular T3 levels.

diogenes profile image
diogenes in reply to jimh111

That is so, but not by changing D2 or D3 levels, but changing the levels of factors that stimulate D2 and otherwise stimulate D3. It is the different stimulants or inhibitors that are key to how the two enzymes react.

jimh111 profile image
jimh111 in reply to diogenes

OK I'll wait for the full paper. This illustrates the importance of studying the full paper.

tattybogle profile image

I think i'll have to wait until 'Tania' reads it and draws me a picture .Have tried to get my head round it using currently available visual aids of 2 Creme Egg's and a pile of 1 p's and 2 p's and a pepper pot.... but am now confused and inexplicably there is only one Creme Egg left.


Gingernut44 profile image
Gingernut44 in reply to tattybogle

Did you do all that while you were up a ladder ?

tattybogle profile image
tattybogle in reply to Gingernut44

No i did all that while i SHOULD be up a ladder, (am only funny when i'm procrastinating)

Life now has 3 modes ,

Up a ladder / Knackered cos i been up a ladder / Procrastinating cos i should be up a ladder.

diogenes profile image
diogenes in reply to tattybogle

I'll try to put it simply. What does the FT3 concentration in blood mean and what does it tell us about what's going on in the tissues? It is basically a kind of general thermometer of the human body, that is, an indication of the average of the T3 supplied by T4-T3 conversion in all the cells plus the T3 supplied direct by the thyroid to satisfy action overall. It's like a high jump bar which must be jumped before one can go onto the next thing. So, first conclusion: blood FT3 cannot show what's going on the the cells individually, but only the average result of what all the cells are doing at that instant. Now each cell/organ group has its own needs, which change moment by moment. This then sets the overall constancy of blood FT3 against the changing short-term needs of each organ. In another metaphor, there has to be a baseline concentration of T3 generally so that each cell can either enhance it by the D2 deiodinase stimulation or reduce it by the cells D3 making rT3 instead from T4. Its like two power stations acting together. If one ups its production(T4-T3), then the other will lower its production, (T4-rT3) to give the correct joint power output. The amount of fuel going to each station needed to work is the same, but the output of each depends on giving the Grid the proper output from both.

tattybogle profile image
tattybogle in reply to diogenes

Thankyou , i do like a nice metaphor. Have upgraded my working model to include a second pepper pot (powerstation) and some peppercorns on a dinner tray... will let you know in about 4 hours if it makes sense now . xx(i've never been quick on the uptake , but i get there)

TSH110 profile image
TSH110 in reply to diogenes

Thanks for that great explanation!

tattybogle profile image

Science moves on , Creme Eggs are an outdated paradigm :)

I'm off to find my diagram of 'which diodinase does what?' that Jim gave me last time i got lost in a circular game of "hypo brain cells trying to understand hypo brain cells"

EDIT. the 'which deiodinase does what' pictures are in this post

TSH110 profile image
TSH110 in reply to tattybogle

You’re cracking me up tatt! I needed a darn good laugh after 8 hours hard lonesome toil at the allotment.

Mollyfan profile image

Thank you for this..... very interesting!!Do you think this has any implications for treatment of people with polymorphisms of DI02/3 ? The only ( blunt) instrument we have at the moment is to increase fT3 by giving liothyronine but this might cause hyperthyroidism in some tissues, especially if there is poor DI03 action. Is anyone looking at any way of mimicking the actions of the deiodenases in the tissues for specific patients and, also, what are the implications of these polymorphisms on people with normally functioning thyroids?

As you can tell I am a novice, but very interested in further research!

TSH110 profile image
TSH110 in reply to Mollyfan

I get the impression a person with a normal thyroid gets around any polymorphisms by making more T3, but if you don’t have a thyroid you can only make so much from T4 and that is not going to be enough for good health if you have poor conversion DIO2 gene combinations and you’re only being given T4 hormone therapy, as no thyroid means no extra T3 to right matters

Lulu2red profile image

Is there a genetic test that covers all polymorphisms involved in thyroid hormones, like DI02/01//03 and MTHR?

diogenes profile image
diogenes in reply to Lulu2red

They would have to be discovered one by one.

helvella profile image
helvellaAdministrator in reply to Lulu2red

Whole genome sequencing is available. Which would, of course, include all polymorphisms.

But it is still quite expensive (around £1,000 for the higher quality version).

And it is all very well owning a library, but you need a catalogue to find the books. And an index to find the pages. We do not yet have anything like complete catalogues and indexes. Which is pretty much what diogenes wrote!

shaws profile image

Thank you diogenes and it sounds hopeful.

vocalEK profile image

I think I have read some other works with Bianco's name on them.

TSH110 profile image

Down there at 8am to receive a horse manure delivery, then constructing water pipe and green netting cloches to keep pesky allium leaf miner off my onions that I planted, mowing lawns, weeding, mulching raised beds with manure, harvesting purple sprouting brócoli & last of mega productive sprouts - I was totally spent by 4pm but managed an hour run after a coffee, a marathon & rest....probably not as hard as harvesting swedes tho, my mother banned their consumption and called them cattle fodder! I feel guilty eating any let alone attempting to grow them with her distain and wagging finger haunting me. I do defiantly grow lots of marigolds tho - she hated them with a passion!

tcpace profile image

So what are the implications of this for people who take only T3 (no T4 to rT3 conversion)?

diogenes profile image
diogenes in reply to tcpace

That is an excellent and vitally important question. If as you say there is no T4 whatsoever, then rT3 cannot be made in a T3-only situation. There are two possible answers: first I think it's rarely seen that there is no T4 whatsoever - ie a tiny bit of thyroid might be still active. Second, the system would work, but the relationship between D2 (now redundant with no thyroid and T4) and D3 (also redundant for making rT3 from T4) is much less stably maintained, because the T3 offered is controlled only by oral dose and not internal T4-T3 or T4-rT3 conversion). Also as you say there ought to be little or no rT3. I'd like TUK posters on long term strictly T3 only and no thyroid to let me see any FT4,FT3,rT3 results they have in the past with date (anonymous if possible).

thyr01d profile image
thyr01d in reply to diogenes

Hi Diogenes, I could look to see if I have results for you if I fit your category. My TSH was over 95 with 95 being coma level yet I was still functioning so endo said my thyroid must have been producing a tiny amount. Have been on T3 only for a few years. If my results would be useful please let me know and I'll send, if I don't hear from you I'll assume the results would not be helpful.

diogenes profile image
diogenes in reply to thyr01d

What I need is someone who has no thyroid, is on T3 only and has TSH, FT3, FT4 and rT3 measurements done at the same time.

thyr01d profile image
thyr01d in reply to diogenes

Can't help you then as I don't have rT3 measured.

TaraJR profile image

A very interesting thread. Like tattybogle I'm also trying to get my head around the science linda96 a thread for you too?

NieuwOndaatje profile image

Many many thanks for this. I'm really looking forward to reading the full article and wondered if there might perhaps be any further recommendations made in terms of potential optimal treatment protocols. I've seen one of Antonio Bianco's earlier mini reviews on "Cracking the Metabolic Code for Thyroid Hormone Signaling" but this looks even more advanced in terms of deiodinase enzymes and the interactions between D2 and D3 at the cellular level. Thanks again and look forward to the long read when it's available.

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