Free triiodothyronine/free thyroxine (FT3/FT4) ratio is strongly associated with insulin resistance in euthyroid and hypothyroid adults: a cross-sectional study
Ladislav Štěpánek Jana Janoutová , Dagmar Horáková , Kateřina Bouchalová, Lubomír Štěpánek , Vladimír Janout , Karel Martiník
Abstract
Introduction: Insulin resistance (IR) is a key and early pathogenetic mechanism of cardiometabolic diseases with huge potential if detected early and mitigated, for lowering the burden of the disease. Available data are conflicting to what extent adult thyroid dysfunction is associated with IR. Therefore, we aimed to investigate the association and to identify which thyroid parameters are predictors of IR. Material and methods: After undergoing basic anthropometric and biochemical studies including thyroid hormones, oral glucose tolerance test (OGTT), and insulin, 1425 middle-aged individuals were divided into three groups according to thyroid parameters: overt hypothyroidism (OH), subclinical hypothyroidism (SH), and euthyroidism (EU).
Results: The homeostasis model assessment of IR (HOMA-IR), fasting insulin, and two-hour glucose levels of OGTT showed a steady, yet insignificant, increase from EU through SH to OH. The strongest noted correlations were those of insulin levels with free triiodothyronine/ /free thyroxine (FT3/FT4) ratio (r = 0.206, p < 0.001) and FT3 (r = 0.205, p < 0.001). Also in the case of HOMA-IR, the only statistically significant correlations were observed for FT3 (r = 0.181, p < 0.001) and the FT3/FT4 ratio (r = 0.165, p < 0.001). Among other thyroid hormones, linear logistic regression proved the FT3/FT4 ratio as the only significant predictor of HOMA-IR (linear coefficient = 5.26, p = 0.027) and insulin levels (linear coefficient = 18.01, p = 0.023), respectively. Thyroid-stimulating hormone was not associated with IR in either correlation or regression analysis.
Conclusions: The FT3/FT4 ratio should be more emphasised in the diagnosis and treatment of thyroid disorders. Patients could benefit from a pharmacological reduction of the FT3/FT4 ratio, potentially leading to a decrease in insulin resistance, and thus a corresponding decrease in the risk of the cardiometabolic diseases. (Endokrynol Pol 2021; 72 (1): 8–13)
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diogenes
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Thanks for posting diogenes but do you think that the 'rules' will be changed? Or just ignored.
"Conclusions: The FT3/FT4 ratio should be more emphasised in the diagnosis and treatment of thyroid disorders. Patients could benefit from a pharmacological reduction of the FT3/FT4 ratio, potentially leading to a decrease in insulin resistance, and thus a corresponding decrease in the risk of the cardiometabolic diseases. (Endokrynol Pol 2021; 72 (1): 8–13)!
Yeah, the study excluded people with low FT4 due to T3 treatment for hypothyroidism. They also excluded people with low FT4 and normal /low TSH who have untreated central hypothyroidism.
There are no scientific benchmarks for healthy vs. unhealthy FT3:FT4 ratios during T3-inclusive therapy because scientists don't study people on long-term T3 treatment. They only study them in rigid clinical trials that last no longer than a few months.
Ratios on T3 therapy are really hard to study, so they'd have to study people on a fixed ratio of synthetic LT3/LT4 combo, or NDT which has a stable ratio. Ratios in real life therapy will largely depend on what ratio of T3 and T4 you are dosing and what your body is doing with that ratio of intake.
People with no measurable FT4 in circulation would have a ratio that is mathematically incalculable because the denominator would be zero. Their thyroid status and risk of insulin resistance are not dependent on T3:T4 ratio! But who knows, it might depend more on T3:T2 ratios... but T2 is too hard to measure, even in research studies
Please correct me if I am wrong, but this implies that it is beneficial to have a lower T3 and higher T4. This is the opposite of what I would expect….?
The closer together the results are, the closer to 1 the ratio is. But, the ratio can be above 1 or below 1. I read it as the lower the ratio of T3 to T4 the less chance of Insulin resistance.
I've just had a look at the actual paper (googled DOI number and found a PDF ) and unless i've misunderstood anything ....i think the results do (unfortunately !)show
'more T3: lessT4' = greater insulin resistance. ie bad
'less T3:more T4'= lower insulin resistance. ie good
BUT ...they were deliberately looking at people with no (diagnosed) thyroid disorders and not taking any thyroid hormone , so the people they classed as 'overtly hypothyroid' did indeed have 'more T3:less T4'
... which is not surprising because that's what happens in a struggling thyroid .. the fT4 drops , then increased TSH prompts thyroid and deiodinase's to increase T3 relative to T4.
In the 'Discussion' section they say...."In hypothyroidism and euthyroidism, as TSH levels rise the FT3/FT4 ratio also rises. Levothyroxinetherapy was proved to decrease the FT3/FT4 ratio [22,23]. Given the association of both hypothyroidism and
the FT3/FT4 ratio with IR, thyroxine supplementation in indicated cases may help not only in achieving euthyroidism but also in improving IR.
So i can't get my head round how these findings about T3:T4 ratio would relate to TREATED hypothyroid people ?
..... but whatever that part means for us .. the good news is ,it's yet another paper showing that T3 levels and T3:T4 ratio's are an accurate /relevant indicator of bodily dysfunction and TSH is NOT ..... and the first hurdle to getting better treatment for us all, is to get TSH officially knocked off it's pedestal.. so i'm happy about the paper, even if they did find something that at first glance might not be helpful to the case for more T3:less T4.
(If i've got that all wrong, i apologise. my brain is a bit melted.
Thank you! That is really helpful. Is there any chance you could give a link to the full paper please?As you say, this is in untreated people and does not reflect the post treatment situation. It may simply reflect the fact that hypothyroid people have more insulin resistance and also have higher T3/T4 ratios.
It is a big stretch( and totally unproven) to suggest that lowering the T3 or raising T4 would reduce Insulin resistance.
Free triiodothyronine/free thyroxine (FT3/FT4) ratio is strongly associated with insulin resistance in euthyroid and hypothyroid adults: a cross-sectional study "
into google and the first result was this "FT3/FT4 - Via Medica Journals " which had a PDF link next to it.
Sorry i can't tell you how to do it properly .. i'm a luddite , so i just go around clicking things to see what happens.
I found this article which explains how complex the relationship is between thyroid hormones and glucose metabolism. Methinks there is more to it than a simple T4 good/T3 bad!
Interesting. Sounds like it has little to do with people actually being treated for hypothyroidism. Those on T3 only will have a FT3/FT4 ratio through the roof compared with those on T4 only! Something doesn't quite stack up here.
Excactly right -- I agree, the scientists should have limited their conclusions to apply only to untreated people. Saying it applies to "diagnosis and treatment" is too sweeping -- it may imply that they are in need of treatment, but it won't necessarily apply to ratios caused by treatment. Our treated FT3:FT4 ratios are dependent on what treatment we are on and how well we absorb and convert thyroid hormones. Many people on desiccated thyroid or T3 will have high FT3:FT4 ratios but will not necessarily be insulin resistant because of it. Also, they excluded many subclinical hyper people with high FT3:FT4 ratios. See my reply in this thread
as in poly cystic ovary syndrome ?I don't think so,.....but i didn't read it all, i just looked at who they included/excluded and the T3:T4;TSH numbers
Don’t have time to look at this in detail but there are studies that show insulin promotes deiodinase. Insulin is high in cases of insulin resistance so this could be causing the high fT3 / fT4 ratio.
I don’t know why they assume it is the fT3 / fT4 that leads to insulin resistance, I won’t have time to track down the full paper and study it.
A further confounding factor is the Thr92Ala DIO2 polymorphism is associated with insulin resistance!
I'm always happy to see articles talk about the clinical relevance of the FT3:FT4 ratio. However, I'd like to add some cautions on the interpretations of the article, based on its blind spots and methodology.
"Patients could benefit from a pharmacological reduction of the FT3/FT4 ratio" -- ha ha not if they already have a LOW FT3/FT4 ratio... "Reduction" is relative. How many of the people in their study had a nonthyroidal illness lowering their FT3 while keeping their FT4 normal?
Also look at how they excluded treated thyroid patients "None of them had a history of thyroid disorders, and they were not treated with any drugs known to affect thyroid function." This changes the applicability of their recommendations, and they should have put that limitation on their conclusion! It is not necessarily about people's ratios while on therapy. They claim incorrectly that their findings apply not only to diagnosis but also to treatment.
So, they say in their full article's final sentence: "The results are valid for middle-aged European adults." -- No, it's only valid for middle-aged European adults who are not being treated with thyroid hormone or diabetes medication.
They also classified them first based on TSH-FT4 parameters, and only later determined that TSH was not the major clinical indicator of insulin resistance. This is a problem because they excluded an important part of the population that was relevant to their study of the FT3:FT4 ratio.
Notice that their definition of hypERthyroidism excludes people with isolated high FT3. Yet this high FT3/FT4 ratio is a feature of high TSHR antibodies in early Graves' hyper to have FT3 elevate before FT4 elevates. It is also seen in people with toxic multinodular goiter or autonomous secreting thyroid nodules.
Somewhat unsurprisingly, with this narrow exclusive definition of hyper, "Only 23 individuals from the whole group met the criteria for hyperthyroidism" out of 1425 people! How many people with an isolated high FT3 alongside a low TSH were excluded from this study? What would their statistics have said if these people's high FT3:FT4 ratios were included?
so glad you have explained some of the things i was thinking, but couldn't even begin to write down in a way that made sense. I wanted to include a picture of table 2 , but couldn't figure out how to copy it (it makes it obvious why the T3:T4 ratio is higher in the 'overt hypo' group.. because the fT4 has dropped in untreated overt hypothyroidism, but the Ft3 does not drop by so much)
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