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3,5-Diiodo-L-thyronine (T2) & Fat Loss

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3,5-Diiodo-L-thyronine (T2) is a putative T3 analog that, in at least one small human study, showed promise as a safe, effective fat-loss aid. Much of the research on T2 comes from the same guys in Italy so there are some legit questions about how reliable it is but there is also a good deal of rat research from other sources that appear to bolster the claims about T2's effects in humans.

 

First the tantalizing human study:

 

J Biol Regul Homeost Agents. 2011 Oct-Dec;25(4):655-60.

3,5-diiodo-L-thyronine increases resting metabolic rate and reduces body weight without undesirable side effects.

Antonelli A, Fallahi P, Ferrari SM, Di Domenicantonio A, Moreno M, Lanni A, Goglia F.

Source

 

Department of Internal Medicine, University of Pisa, Pisa, Italy. alessandro.antonelli@med.unipi.it

Abstract

 

Recently, it was demonstrated that 3,5-diiodo-L-thyronine (T2) stimulates the resting metabolic rate (RMR), and reduces body-weight gain of rats receiving a high-fat diet. The aim of this study is to examine the effects of chronic T2 administration on basal metabolic rate and body weight in humans. Two euthyroid subjects volunteered to undergo T2 administration. Body weight, body mass index, blood pressure, heart rate, electrocardiogram, thyroid and liver ultrasonography, glycemia, total cholesterol, triglycerides, free T3 (FT3), free T4 (FT4), T2, thyroid stimulating hormone (TSH) and RMR were evaluated at baseline and at the end of treatment. RMR increased significantly in each subject. After continuing the T2 treatment for a further 3 weeks (at 300 mcg/day), body weight was reduced significantly (p

 

PMID: 22217997

 

 

Pretty cool. And the murine model to support the human study results:

 

FASEB J. 2005 Sep;19(11):1552-4. Epub 2005 Jul 12.

3,5-diiodo-L-thyronine powerfully reduces adiposity in rats by increasing the burning of fats.

Lanni A, Moreno M, Lombardi A, de Lange P, Silvestri E, Ragni M, Farina P, Baccari GC, Fallahi P, Antonelli A, Goglia F.

Source

 

Dipartimento di Scienze della Vita, Seconda Università di Napoli, Caserta, Italy. antonia.lanni@unina2.it

Abstract

 

The effect of thyroid hormones on metabolism has long supported their potential as drugs to stimulate fat reduction, but the concomitant induction of a thyrotoxic state has greatly limited their use. Recent evidence suggests that 3,5-diiodo-L-thyronine (T2), a naturally occurring iodothyronine, stimulates metabolic rate via mechanisms involving the mitochondrial apparatus. We examined whether this effect would result in reduced energy storage. Here, we show that T2 administration to rats receiving a high-fat diet (HFD) reduces both adiposity and body weight gain without inducing thyrotoxicity. Rats receiving HFD + T2 showed (when compared with rats receiving HFD alone) a 13% lower body weight, a 42% higher liver fatty acid oxidation rate, appoximately 50% less fat mass, a complete disappearance of fat from the liver, and significant reductions in the serum triglyceride and cholesterol levels (-52% and -18%, respectively). Thyroid hormones and thyroid-stimulating hormone (TSH) serum levels were not influenced by T2 administration. The biochemical mechanism underlying the effects of T2 on liver metabolism involves the carnitine palmitoyl-transferase system and mitochondrial uncoupling. If the results hold true for humans, pharmacological administration of T2 might serve to counteract the problems associated with overweight, such as accumulation of lipids in liver and serum, without inducing thyrotoxicity. However, the results reported here do not exclude deleterious effects of T2 on a longer time scale as well as do not show that T2 acts in the same way in humans.

 

PMID: 16014396

 

FFT

 

 

So it appears to potently stimulate hepatic fat oxidation...sounds like it might pair well with AAS that induce reverse cholesterol transport bringing fat from adipose tissue to the liver...

 

More Italian research indicating that T2 may be a metabolite of T3 in vivo and is partially responsible for T3's effects on RMR.

 

Endocrinology. 2002 Feb;143(2):504-10.

Are the effects of T3 on resting metabolic rate in euthyroid rats entirely caused by T3 itself?

Moreno M, Lombardi A, Beneduce L, Silvestri E, Pinna G, Goglia F, Lanni A.

Source

 

Dipartimento di Scienze Biologiche ed Ambientali, Università degli Studi del Sannio, 82100 Benevento, Italy.

Abstract

 

Because we previously reported that T3 and 3,5-diiodo-L-thyronine (3,5-T2) both increase resting metabolic rate (RMR), 3,5-T2 could be another thyroidal regulator of energy metabolism. This effect of 3,5-T2 is evident in rats made hypothyroid by propylthiouracil and iopanoic acid, not in normal euthyroid (N) rats. Possibly, under euthyroid conditions, active 3,5-T2 may need to be formed intracellularly from a precursor such as T3. We tested this hypothesis by giving a single injection of T3 to N rats and comparing the time course of the variations in RMR with those of the changes in the serum and hepatic levels of 3,5-T2. Acute injection had an evident effect on RMR, 25 h earlier, in N rats than in rats made hypothyroid by propylthiouracil and iopanoic acid, maximal values (+40%) being reached in the former at 24-26 h. In N rats, the simultaneous injection of actinomycin D with the T3 inhibited the late part of the effect (after 24 h) more strongly than the early part (14-24 h). In serum and liver, 3,5-T2 levels were increased significantly at 12-24 h after T3 injection into N rats, a time at which RMR was rising rapidly to peak. These results seem to indicate that when T3 is injected into N animals, not all the effects on RMR are attributable to T3 itself, the early effect presumably being largely because of its in vivo deiodination to 3,5-T2. Because the effects of T3 and 3,5-T2 are additive, in N rats, the two iodothyronines probably cooperate in vivo to determine the total metabolic rate.

 

PMID: 11796504

 

FFT

 

From the FT, possible MOA of T2 contrasted with T3

Turning now to 3,5-T2, we can say that, in contrast to T3, its effects on RMR seem to be attributable to nuclear-independent mechanisms. Some data support this conclusion. The affinity of 3,5-T2 for nuclear TRs is very low. It has been shown that TRβ1 has low affinity for 3,5-T2, with relative affinity constants 0.15% of that for T3. More recently, Ball et al. have shown that TRβ2 binds 3,5-T2 more avidly than do the other TRs, this apparent affinity remains substantially (40-fold) less than that for T3. The same authors reported that 3,5-T2 is approximately 1000-fold less potent than T3 in dissociating TRβ1 homodimers from a TRE, thus indicating that the relative ability of 3,5-T2 to bind to and produce conformational changes in a TR is consistent with its relatively low binding affinity. Moreover, an extranuclear mechanism of action of 3,5-T2 fits well with our data showing that 3,5-T2 binds to mitochondrial components and with our more recent data showing that 3,5-T2 has a very rapid effect on glucose-6-phosphate-dehydrogenase activity that is independent of protein synthesis. In addition, 3,5-T2 is able to stimulate the activity of the cytochrome c oxidase complex, and the subunit Va of this complex has been identified as a binding site for 3,5-T2. Recently, Kadenbach and co-workers have suggested that 3,5-T2 is able to decrease the efficiency of the cytochrome oxidase complex by inducing a reduction in proton-pumping.

 

Some more general information about the thyromimetic properties of T2

 

J Mol Endocrinol. 1997 Oct;19(2):137-47.

3,5-Diiodo-L-thyronine (T2) has selective thyromimetic effects in vivo and in vitro.

Ball SG, Sokolov J, Chin WW.

Source

 

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Abstract

 

Recent data have suggested that the iodothyronine, 3,5-diiodo-l-thyronine (T2), has selective thyromimetic activity. In vivo, T2 has been shown to suppress TSH levels at doses that do not produce significant peripheral manifestations of thyroid hormone activity. Furthermore, T2 has been shown to produce smaller increments in peripheral indices of thyroid status than does T3, when doses resulting in equivalent suppression of circulating TSH are compared. We have assessed the selective thyromimetic activity of T2 in vivo and in vitro, and performed in vitro studies to assess the potential molecular basis for these selective properties. T2 was 100-fold less potent than T3 in stimulating GH mRNA levels in GH3 cells. In contrast, the iodothyronines were almost equivalent in their ability to downregulate TRbeta2 mRNA levels in this cell line. Both 3,3'-diiodo-L-thyronine and thyronine exhibited no significant thyromimetic effects on either process. In vivo, doses of T2 and T3 that were equivalent in their induction of hepatic malic enzyme (ME) mRNA did not produce equivalent suppression of circulating TSH, with T2 being only 27% as effective as T3. T2 was up to 500-fold less potent than T3 in displacing [125I]-T3 from in vitro translated specific nuclear receptors (TRs) and GH3 cell nuclear extracts. Electrophoretic mobility shift assays, assessing the ability of T2 to produce dissociation of TRbeta1 homodimers from inverted palindrome T3 response elements, indicated that T2 was also 1000-fold less potent than T3 in this respect. These data confirm that T2 has significant thyromimetic activity, and that this activity is selective both in vivo and in vitro. However, there are no data to support a selective central effect, T2 being relatively more potent in stimulating hepatic ME mRNA than in suppression of TSH in vivo. The basis for this differential thyromimetic activity is not selective affinity of the different TR isoforms for T2, or divergent properties of T2 in competitive binding and functional assays in vitro.

 

PMID: 9343306

 

FFT

 

 

An interesting nugget from the FT, this would appear to support the Italian's finding that T2 was not suppressive of endogenous thyroid production at physiologic doses.

 

However, we show that at in vivo doses of T2 and T3 resulting in equivalent induction of ME gene expression, T2 is significantly less potent in suppressing plasma TSH.

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I've been playing around with SAN's T2 Xtreme product for the last couple of weeks, escalating the dose from 100 to 300mcg...so far, I've noticed very little in the way of systemic metabolic stimulation indicators with the one exception that my resting pulse appears to be elevated by about 10BPM, something that I did not connect to the T2 until just now...I would say, subjectively, that it is helping to lean me out. Granted I've got lots of confounders but Mrs. Benson independently reported the same thing and she has far fewer confounders...she also doesn't really know what T2 is or how it is supposed to work so the placebo effect may be less strong in her than in me.

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I can only say that it is highly suspect that all the research comes from one lady in Italy and that the human data was not published in an International peer-reviewed journal, but a backyard "science" journal... plus, my trials with T2 in the past yielded "weight loss" only in my purse (same for a couple of friends)

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5. 3,3'-Diiodo-L-Thyronine

Pros: Can help manage hyperthyroidism

Cons:Less than 3% of the calorigenic activity of T4; No increase in BMR (Basal Metabolic Rate) en vivo; Decreases circulating levels of T4

References: http://endo.endojournals.org/content/64/1/62.short

 

6. 3,5-Diiodo-L-Thyronine

Pros: Can help manage hyperthyroidism

Cons: Goitrogenic (Directly suppresses the thyroid gland); Less than 3% of the calorigenic activity of T4; No increase in BMR en vivo; Decreases circulating levels of TSH

References:

(1) http://endo.endojournals.org/cgi/content/abstract/64/1/62

 

 

From: http://hightowerpharmacology.blogspot.com/2011/11/top-8-worst-stimulants-of-all-time.html

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6. 3,5-Diiodo-L-Thyronine

Pros: Can help manage hyperthyroidism

Cons: Goitrogenic (Directly suppresses the thyroid gland); Less than 3% of the calorigenic activity of T4; No increase in BMR en vivo; Decreases circulating levels of TSH

 

Interesting. Those claims would appear to be at odds with the data presented above.

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I can only say that it is highly suspect that all the research comes from one lady in Italy and that the human data was not published in an International peer-reviewed journal' date=' but a backyard "science" journal[/quote']

 

While not JAMA or Nature, the Journal of Biologic Regulators & Homeostatic Agents appears to be both international and peer-reviewed. Many of the same researchers published their earlier murine study in The FASEB Journal which is not exactly bathroom reading...I do agree that there needs to be additional, well-controlled studies of this compound before we can bank it but the research I've seen so far seems to support, rather than contradict, the in vivo human finding of the Italian study.

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While not JAMA or Nature' date=' the [i']Journal of Biologic Regulators & Homeostatic Agents[/i] appears to be both international and peer-reviewed. Many of the same researchers published their earlier murine study in The FASEB Journal which is not exactly bathroom reading...I do agree that there needs to be additional, well-controlled studies of this compound before we can bank it but the research I've seen so far seems to support, rather than contradict, the in vivo human finding of the Italian study.

 

actually not, if you look careful through the inititial studies, you will realize that they used hypothyroid rodents. Also if you calculated HEDs, the human subjects would have had to take 10x more to see effects (with thyroid stuff HED calculations are yet not always reliable). Then there is the problem with the half-life. That alone renders the 3.3 totally useless

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actually not' date=' if you look careful through the inititial studies, you will realize that they used hypothyroid rodents. [/quote']

 

Looks like they used both although 3,5 T2 clearly has bigger effects in hypothyroid subjects.

 

Also if you calculated HEDs, the human subjects would have had to take 10x more to see effects (with thyroid stuff HED calculations are yet not always reliable). Then there is the problem with the half-life. That alone renders the 3.3 totally useless

 

3,3 T2 does not have any useful activity in humans that I am aware of.

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Rat study but interesting nonetheless.

 

Biochim Biophys Acta. 2013 May;1832(5):674-84. doi: 10.1016/j.bbadis.2013.01.023. Epub 2013 Feb 8.

3,5-Diiodo-l-thyronine ameliorates diabetic nephropathy in streptozotocin-induced diabetic rats.

Shang G, Gao P, Zhao Z, Chen Q, Jiang T, Zhang N, Li H.

Source

 

Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, People's Republic of China.

Abstract

 

3, 5-Diiodothyronine (T2), a natural metabolite of triiodothyronine (T3) from deiodination pathway, can mimic biologic effects of T3 without inducing thyrotoxic effects. Recent studies revealed T3 acted as a protective factor against diabetic nephropathy (DN). Nevertheless, little is known about the effect of T2 on DN. This study was designed to investigate whether and how T2 affects experimental models of DN in vivo and in vitro. Administration of T2 was found to prevent significant decrease in SIRT1 protein expression and activity as well as increases in blood glucose, urine albumin excretion, matrix expansion, transforming growth factor-β1 expression, fibronectin and type IV collagen deposition in the diabetic kidney. Concordantly, similar effects of T2 were exhibited in the cultured rat mesangial cells (RMC) exposed to high glucose and that could be abolished by a known SIRT1 inhibitor, sirtinol. Moreover, enhanced NF-κB acetylation and JNK phosphorylation present in both diabetic rats and high glucose-treated RMC were distinctly dampened by T2. Collectively, these results suggested that T2 was a protective agent against renal damage in diabetic nephropathy, whose action involved regulation of SIRT1.

 

Copyright © 2013 Elsevier B.V. All rights reserved.

 

PMID: 23416120

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I've never tried T2 alone, and I probably wouldn't given the price of the solo products I see available so far, but I have always had tremendous success with Alpha-T2 with no change in diet. Unfortunately you seem to be interested in 3,5-T2, though, a compound I've never tried.

 

To be honest, I probably would not be interested in using (3,3-)T2 alone unless it was sold for about $5-10 for a run. Even then I'd still use it on top of something like E/C. I haven't heard enough positive reviews about Shift, for instance, the PES/SS product that is only 3,3-T2.

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Elevated 3,5-Diiodothyronine Concentrations in the Sera of Patients with Nonthyroidal Illnesses and Brain Tumors

 

Graziano Pinna,

Harald Meinhold,

Luis Hiedra,

Rudy Thoma,

Thomas Hoell,

Klaus-Jürgen Gräf,

Gisela Stoltenburg-Didinger,

Murat Eravci,

Hans Prengel,

Oliver Brödel,

Reinhard Finke and

Andreas Baumgartner

 

- Author Affiliations

 

Department of Radiological Diagnostics and Nuclear Medicine, Neurosurgery (T.H.), Neuropathology (G.S.-D.), and Endocrinology (R.F.), Universitätsklinikum Benjamin Franklin, Free University of Berlin; the Department of Medicine (K.-J.G.), Universitätsklinikum Rudolf Virchow, Humboldt University of Berlin; and Formula GmbH (R.T.), Berlin, Germany

 

Address all correspondence and requests for reprints to: Dr. A. Baumgartner, Department of Radiological Diagnostics and Nuclear Medicine and Radiochemistry, Hindenburgdamm 30, 12200 Berlin, Germany.

 

Abstract

 

This study reports the development of a highly sensitive and reproducible RIA for the measurement of 3,5-diiodothyronine (3,5-T2) in human serum and tissue. The RIA employs 3-bromo-5-[125I]iodo-L-thyronine (3-Br-5-[125I]T1) as tracer, which was synthesized carrier free by an interhalogen exchange from 3,5-dibromo-L-thyronine (3,5-Br2T0). The detection limits were 1.0 fmol/g and 0.8 pmol/L in human brain tissue and serum, respectively. T3, diiodothyroacetic acid, and 3-monoiodothyronine cross-reacted with a 3,5-T2 antibody to the extent of 0.06%, 0.13%, and 0.65%, respectively.

 

Serum concentrations of 3,5-T2 were measured in 62 healthy controls and 4 groups of patients with nonthyroidal illness, i.e. patients with sepsis (n = 24), liver diseases (n = 23), head and/or brain injury (n = 15), and brain tumors (n = 21). The mean serum level of 3,5-T2 in the healthy subjects was 16.2 ± 6.4 pmol/L. Concentrations of 3,5-T2 were significantly elevated in patients with sepsis (46.7 ± 48.8 pmol/L; P < 0.01), liver diseases (24.8 ± 14.9 pmol/L; P < 0.01), head and/or brain injury (24.1 ± 11.3 pmol/L; P < 0.05), and brain tumors (21.6 ± 4.8 pmol/L; P < 0.01). In all 4 patient groups, serum levels of T3 were significantly reduced, confirming the existence of a low T3 syndrome in these diseases. Serum concentrations of 3,5-T2 were significantly elevated in patients with hyperthyroidism (n = 9) and were reduced in patients with hypothyroidism (n = 8). The levels of T4, T3, and 3,5-T2 were measured in normal human tissue samples from the pituitary gland and various brain regions and in brain tumors. In normal brain tissue, the concentrations of 3,5-T2 ranged between 70–150 fmol/g, and the ratio of T3 to 3,5-T2 was approximately 20:1. In brain tumors, however, T3 levels were markedly lower, resulting in a ratio of T3 to 3,5-T2 of approximately 1:1.

 

Recent findings suggest a physiological, thyromimetic role of 3,5-T2, possibly stimulating mitochondrial respiratory chain activity. Should this prove to be correct, then the increased availability of 3,5-T2 in nonthyroidal illness may be one factor involved in maintaining clinical euthyroidism in patients with reduced serum levels of T3 during nonthyroidal illness.

 

likewise interesting,

 

Are the Effects of T3 on Resting Metabolic Rate in Euthyroid Rats Entirely Caused by T3 Itself?

 

Maria Moreno,

Assunta Lombardi,

Luca Beneduce,

Elena Silvestri,

Graziano Pinna,

Fernando Goglia and

Antonia Lanni

 

- Author Affiliations

 

Dipartimento di Scienze Biologiche ed Ambientali (M.M., E.S., F.G.), Università degli Studi del Sannio, 82100 Benevento, Italy; Dipartimento di Scienze della Vita (A.La.), Seconda Università degli Studi di Napoli, 81100 Caserta, Italy; Dipartimento di Fisiologia Generale ed Ambientale (A.Lo., L.B.), Università di Napoli Federico II, 80134 Napoli, Italy; and Department of Radiology and Nuclear Medicine (G.P.), Benjamin Franklin Medical Center, Free University of Berlin, 12200 Berlin, Germany

 

Address all correspondence and requests for reprints to: Antonia Lanni, Dipartimento di Scienze della Vita, Seconda Università degli Studi di Napoli, Via Vivaldi 43, 81100 Caserta, Italy. E-mail: antonia.lanni@unina2.it

 

Abstract

 

Because we previously reported that T3 and 3,5-diiodo-l- thyronine (3,5-T2) both increase resting metabolic rate (RMR), 3,5-T2 could be another thyroidal regulator of energy metabolism. This effect of 3,5-T2 is evident in rats made hypothyroid by propylthiouracil and iopanoic acid, not in normal euthyroid (N) rats. Possibly, under euthyroid conditions, active 3,5-T2 may need to be formed intracellularly from a precursor such as T3. We tested this hypothesis by giving a single injection of T3 to N rats and comparing the time course of the variations in RMR with those of the changes in the serum and hepatic levels of 3,5-T2. Acute injection had an evident effect on RMR, 25 h earlier, in N rats than in rats made hypothyroid by propylthiouracil and iopanoic acid, maximal values (+40%) being reached in the former at 24–26 h. In N rats, the simultaneous injection of actinomycin D with the T3 inhibited the late part of the effect (after 24 h) more strongly than the early part (14–24 h). In serum and liver, 3,5-T2 levels were increased significantly at 12–24 h after T3 injection into N rats, a time at which RMR was rising rapidly to peak. These results seem to indicate that when T3 is injected into N animals, not all the effects on RMR are attributable to T3 itself, the early effect presumably being largely because of its in vivo deiodination to 3,5-T2. Because the effects of T3 and 3,5-T2 are additive, in N rats, the two iodothyronines probably cooperate in vivo to determine the total metabolic rate.

I agree that all that suggests that it works, but I still doubt it will anywhere close to "T3-like" effects. Otherwise it would long have become all the rage, which it clearly has not (although many people have used it)...

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on another note. You can get 500mg of T2 for €150 even if you buy it directly over at sigma aldrich, this is equivalent to 166 bottles of T33, and still ~28 bottles of SanT2... just saying, after all I want you not to waste your money, when you test it for me ;)

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on another note. You can get 500mg of T2 for €150 even if you buy it directly over at sigma aldrich' date=' this is equivalent to 166 bottles of T33, and still ~28 bottles of SanT2... just saying, after all I want you not to waste your money, when you test it for me ;)[/quote']

 

Much appreciated Professor.

 

I agree, the stuff is not the metabolic sledgehammer that T3 is but if it can boost RMR by 3-4% and do it in a way that doesn't reduce natural thryroid function, that might not be a bad thing...

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Much appreciated Professor.

 

I agree, the stuff is not the metabolic sledgehammer that T3 is but if it can boost RMR by 3-4% and do it in a way that doesn't reduce natural thryroid function, that might not be a bad thing...

 

hmm... just saw I did not post the study on ATP !? Well, I will look it up later again, but in fact T2 interacts with COX and does thereby directly cause "energy wasting", so I am actually tempted to get myself a batch of T2 from sigma aldrich and experiment with 500mcg/day ;) After all a small boost is way more than the rest of the current fat burner generation can do (all useless stims)

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Interesting, I just bought a product that has both 3,3 and 3,5, albeit in small amounts (considering the prop blend was on 335mg including caffeine bleh) but it only set me back $4 so what do I care.

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