A breakthrough-like effect of metformin reduces peripheral resistance to triiodothyronine in euthyroid, non-insulin-resistant, T2 diabetes

[helvella]

My main aim here is to identify to anyone interested that metformin appears to have an impact of T3 levels.

Whether the hypotheses of the paper make any sense of that observation is, I fear, rather more questionable. (Though I accept is was very much acknowledged to be a pilot study.)

A breakthrough-like effect of metformin reduces peripheral resistance to triiodothyronine in euthyroid, non-insulin-resistant, type 2 diabetic patients

in Endocrine Connections

Authors:Melinda Kertész 1 , Szilárd Kun 1 , Eszter Sélley 1 , Zsuzsanna Nagy 1 , Tamás Kőszegi 2 , and István Wittmann 1

DOI: doi.org/10.1530/EC-21-0218

Volume/Issue: Volume 10: Issue 7

Page Range: 782–788

Article Type: Research Article

Online Publication Date: 21 Jul 2021

Copyright: © The authors 2021

Abstract

Background

Type 2 diabetes is characterized, beyond the insulin resistance, by polyhormonal resistance. Thyroid hormonal resistance has not yet been described in this population of patients. Metformin is used to decrease insulin resistance, and at present, it is assumed to influence the effect of triiodothyronine, as well.

Methods

In this open-label, pilot, hypothesis-generating, follow-up study, 21 patients were included; all of them were euthyroid with drug naïve, newly diagnosed type 2 diabetes. Before and after 4 weeks of metformin therapy, fructosamine, homeostasis model assessment for insulin resistance (HOMA-IR), thyroid hormones, T3/T4 ratio, and TSH, as well as blood pressure and heart rate using ambulatory blood pressure monitor were measured. We also conducted an in vitro study to investigate the possible mechanisms of T3 resistance, assessing T3-induced Akt phosphorylation among normal (5 mM) and high (25 mM) glucose levels with or without metformin treatment in a human embryonal kidney cell line.

Results

Metformin decreased the level of T3 (P < 0.001), the ratio of T3/T4 (P= 0.038), fructosamine (P= 0.008) and HOMA-IR (P= 0.022). All these changes were accompanied by an unchanged TSH, T4, triglyceride, plasma glucose, bodyweight, blood pressure, and heart rate. In our in vitro study, T3-induced Akt phosphorylation decreased in cells grown in 25 mM glucose medium compared to those in 5 mM. Metformin could not reverse this effect.

Conclusion

Metformin seems to improve T3 sensitivity in the cardiovascular system in euthyroid, type 2 diabetic patients, the mechanism of which may be supracellular.

Keywords: insulin resistance; metformin; ratio of T3/T4; triiodothyronine resistance; type 2 diabetes mellitus

Full text freely available here:

ec.bioscientifica.com/view/...

[Katurajo1]

This is an interesting study, I hope they can conduct it on a larger population and include non-euthyroid patients as well. Seems to me that this shows that metformin helps decrease t3 resistance and allows the tissues to use it as they need rather than having a high t3 serum level in the blood. Is that your takeaway @helvella ? I wonder though about using post myocardial infarction patients who typically need additional t3 to heal, I feel like maybe those patients should not be included, just my thoughts. Many holistic doctors advise metformin or even berberine for general anti-aging and I’m wondering if this has something to do with that. Very very interesting study.

[humanbean]

A chubby acquaintance of mine started taking metformin about 4 or 5 years ago. In no time at all he had slimmed down an amazing amount. I asked his wife if he'd changed his diet and apparently he hadn't, the only change was taking metformin, and she said it is known to slim some people down.

I have no idea if that acquaintance is hypothyroid. He's not the kind of person I would discuss such things with. But the effect on him of the metformin is apparently reasonably common.

[jgelliss]

Wow !!!! Great Study Helvella and very very interesting. I'm just wondering for those of us either sole on T4 or T3 and T4 combo does that mean that the T3 gets utilised in a more sufficient way with metformin or berberine ?

Great and very informative useful studies . Thank You.

[helvella Administrator Thyroid UK in reply to jgelliss]

I'd be very wary of taking any of this at face value.

Part of me wonders why euthyroid people need to have T3 resistance addressed?

Their T3 lowered - but, maybe, rather than reducing need for T3 by dosing with metformin, they needed more to be T3 available? Whether they currently have low iodine, low T4, or whatever else!

Need to read again and see what I make of it then.

[jgelliss in reply to helvella]

You make a very good point . Thank you Helvella.

[LindaC in reply to helvella]

Once, inevitably, becoming T2D - after years of pleading for medical help re weight gain... yeah! - I refused Metformin [and a statin] every time it was recommended. (My slim mother died of pancreatic ca, following years on Metformin... due to Low BP drugs [she didn't have High BP... did what doctor said, despite 'drop attacks' - heart issues and ++]!)

From July 2015 I went from HbA1c of 71 [highest ever] to 39 in 4 months, then to 37. Kept it all going great until a surprise illness 'took me over' during Aug 2016. Back piled on the weight [never been obese until hypothyroid] - wouldn't shift again [as from 2003 to 2015]. It's now - Feb to June and still losing - back off again and T2D has again retreated...! It CAN be seen off with diet alone + I do take berberine... just my 2 cents.

[Miffie in reply to LindaC]

I have read in the past that berberine is as effective as Metformin in helping diabetes patients to control blood glucose levels.Despite over a decade of diet I have yet to put T2 in remission. What do you think I am doing wrong? I never had HBA1c over 52 when diagnosed and was invariably around mid forties until recently. Six months ago up to 56 Last week id was 65! I have read low ferritin can cause an increase in HBA1c and wonder if this is my problem. I had testing in June when ferritin was 13 range 10-204. GP happy but endo asked them to treat to increase to 30. I was given a 28 day course of ferrous sulphate. Last tested last week ferritin now 12.6 range 10-204 and GP has said it’s perfect!

Seeing the diabetic nurse next week so interested in any suggestions you have re diet I have recently reduced from 800 a day to 500 a day . Previously I was on LCHF.

[helvella Administrator Thyroid UK in reply to Miffie]

What is wrong is your GP?

NICE has said ferritin below 30 should be treated.

But the eternal problem is that even had your ferritin risen sufficiently, they'd have stopped you supplementation and it would have dropped. The iron rollercoaster.

Choose an iron supplement you tolerate well - take enough to get your ferritin up. And, when you get there, reduce the dose but don't stop. Keep going on a maintenance dose. It takes months and months, maybe years, to get ferritin to a good level. A one month course shows the appalling level of understanding.

This link might help a little though it is rather old and needs revision.

helvella - Iron Document

Information collected and linked regarding iron and iron supplementation.

dropbox.com/s/4d885frbic4z8...

It might not sort out your T2, but it needs sorting regardless.

And make sure you get tested sufficiently frequently - excess iron is bad for you.

[Miffie in reply to helvella]

Thanks helvella , my GP surgery appears to now be run by the anti NICE brigade. To suggest as a patient any reading and understanding of NICE guidelines is usually met with BUT, followed by a feeble reason. It’s much the same when questioning why below reference range test results are ‘perfect’ even if the link they provide to labtestsonline.com states otherwise.

Sadly in my rural area I have no other choice.

I will be speaking to the endo who asked them to raise it soon and will be interested to know his reaction.

In the meantime I will start self sourcing a suitable iron supplement. I have been treated several times for iron deficiency. I always hoped my diet should keep it stable. As you say regular testing is essential as I have ckd so need to keep ferritin at below 100.

Thanks for the link, your info is always appreciated and I find always spot on!

[LindaC in reply to Miffie]

Ferritin perfect!? Eek! Apologies, years not being dx hypothyriod = can't precis now!

Yes, my HbA1c was late 40's then within 50's until that one time... huge shock, yet inevitable given the bizarre weight gain. Nothing lost over a period of 12 yrs, simply nothing would shift it: exemplary dietary habits, PLUS huge amounts of resistance training = still nothing more than a couple of lbs up and down! I was very fit though, that's what exercise is for, yet with exemplary dietary habits it was unfathomable.

If you look down my list of posts to 2015/16? I was eating x3 times each day back then, (10.30 am, 3.30 pm and 8.30 pm - variable to half an hour or any timings of your choice - but ensuring 5 hrs in between each meal - NOTHING whatsoever in between]. Medicine could offer nothing and, if it was injections or 'fat slick' stuff, I wouldn't have taken them. GP freaked out when I mentioned 'intermitting fasting'. even said, "What if you're hungry at 9.30 am"? I replied, "I'll wait"!

So, doing something different and timings = lost weight NO PROBLEM - different foods and relatively small amounts. [Nowhere near as little as you're eating! ] and around 50 lbs came off in 4 months and no, I hadn't been stuffing my face at all. Loved eating this way - no issue with going out - just choosing LC, MP and Higher Fat at the right time of day.

It stayed off and I was still losing until severe vertigo - < Aug 2016 - GP said, due to vomiting, eat starches. What I fool I was to listen - too ill to even consider that a Slimasoup and fasting would have been the way to go. In 13 months, 60 lbs back on but not too bad HbA1c for a little while: I was devastated because I went back to my former way of eating. Medics seem to 'think' that people like us 'stuff our faces with junk food'. NOOO! So I was back to being unable to shift weight... again!

Feb 2021: general blood #s not so good to me [I keep check now!], so went to eating twice a day at 2.30 pm and 7.30 pm [give or take for my convenience, say a half hour to an hour either way... once in a while]. I had less to lose this time, err like 7 lbs lost in all of that time above... again, whatever I'd done had made little to no difference.

Feb - July 2021 = 48 lbs down, Now 53 down (and the 7 lb already off) + still going down. I'm choosing a target now...! Write down weight, somehow committing it to paper seems to make a difference! Oh, HbA1c back down to 39; went lower in the past so hoping this time too.

DO SOMETHING TOTALLY DIFFERENT + REMEMBER, TIMING IS EVERYTHING! The only snack ever needed it the glycogen thrown out by the liver... BEST OF xox

I am so sorry for the capitals and directness - it's not you that I'm directing this to BUT the Medics who refuse to accept people gain weight for all sorts of HORMONAL reasons. xox 🦋☘️🌹

[Miffie in reply to LindaC]

That’s really good to hear, my diabetic nurse is really good with my intermittent fasting she has no problems that I eat in a six / seven hour window, I have usually two meals one at 13:00 ish and the at 18:00 ish. Only naughty bits are black coffee about 10:00 and then another 3 cups across the day. For my current excess weightI blame the GP who last year decided I no longer needed to be treated for hypothyroidism so left with nothing for months then a massive 3+stone weight gain in 3 months. This is what I am trying to shift now. Just no joy but fingers crossed I am coming up to getting my thyroid optimal again as the endo is happy to have me on levo plus my self sourced ndt. Leaving the GP no room to argue really.

Good to know your IF is going so well.

[SlowDragon Administrator in reply to Miffie]

Low ferritin, folate, B12 and vitamin D all directly linked to being hypothyroid

Are you now back on levothyroxine

[Miffie in reply to SlowDragon]

Yes back on it albeit a tiny dose , 100 mcg but at least the endo told GP he is happy for me to top up with ndt.

[LindaC in reply to Miffie]

Great to hear nurse + endo - some of them have latched on to IF and EF. I sometimes throw in an Extended fast, did a couple of 42 hours but found it unnecessary - the odd 24 I may do, just for health reasons.

Yes, I get you entirely - and really feel for you - when a lot of weight comes on, it's so awful! I desperately needed thryoid hormones - ignored for several years. Were it not for Dr S [Armour] and Dr P [T3] ... I've no idea where I'd be now. Do take care xox 🦋☘️

[LindaC in reply to Miffie]

Eek, sorry I've added to my message - the BOLDED at end - apologies, carried away re medics!! 😅👽

[Angel_of_the_North in reply to helvella]

Or are they actually euthyroid or do they just have TSH somewhere in range

[SilverAvocado in reply to Angel_of_the_North]

I thought that, too. I find the term "euthyroid" quite depressing, now, because it is so often inaccurate.