Allegedly 'Harmless' Thyroid-Based Fat Burner 3,5-T2 Works Like a Charm, While Commonly Sold 3,3-T2 Could Mess W/ Your Blood Glucose Levels, Liver & Body Fat + Muscle

These are the kind of abs, you will see on products with T2 and/or T2 and other alleged fat-burners. Don't be fooled by the ads - even if it's the actually active form of diiodothyronine (T2), namely 3,5-T2, you're buying, the pills alone won't get you to the sub-10% body fat range you  may be dreaming of.

I've written about the thyroid hormone metabolite diiodothyronine aka T2 before. Accordingly, you will probably know that it has long been thought of as an inactive byproduct of the thyroid hormone metabolism (read previous T2-articles). You will also be aware of the fact that research shows that (a) this is not the case and that (b) only one of its two forms, namely 3,5-diiodothyronine (3,5-T2) shares the fat burning, metabolic effects of its big brother triiodothyronine aka T3.

Just like me, you probably don't know, however, why supplement companies are still stupid enough to use both 3,5- and 3,3-diiodothyronine in their allegedly fat burning supplements - "stupid", because we already knew it has no effect and even more stupid, since a recent study from the Universidade de São Paulo and the Houston Methodist Research Institute has shown that it will, in total contrast to 3,5-T2, of which the latest research by da Silva Teixeira et al. shows that it will reduce the blood glucose levels independently of insulin sensitization, impair the metabolism of glucose.

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Yes, you read that right: While 3,5-T2 burns fat (especially in the liver) and increases your metabolism, its cousin 3,3-T2 will do nothing for your BMR/RMR + glucose and fatty acid metabolism and can, on top of that, even impair your glucose metabolism and, as the data in Figure 1 shows, increase the amount of liver fat and food intake.

Figure 1: Effects of T3 (DT3 at 0.75 mg/kg), 3,5-T2 (D3,5-T2 at 1.25 and 12.5 mg/kg) and 3,3 T2 (D3,3-T2 at 1,25 mg/kg) on (A) body weight trajectory, (B) body fat (%), lean mass (%), (D) body temperature, (E) food intake, (F) liver fat, (G) heart weight & (H) TSH of diet-induced obese mice (da Silva Teixeira. 2016).

I guess this negative effect on your glucose metabolism alone should be reason enough to avoid supplements with the commonly used combination of 3,3- and 3,5-T2.

In man, there's a J-shaped correlation between blood glucose 3,5-T2 in (open boxes: all subjects; closed boxes: euthyroid patients), but no significant correlation with waist circumference (a proxy of visceral fat) and subcutaneous fat according to Pietzner et al. (2015).

What dosages are we talking about? Unfortunately, the study at hand provides no guideline as to how much of this thyroid metabolite is actually necessary to boost your overall, fat and glucose metabolism, because the regular way to calculate human equivalent doses (HED | learn how to do it) seems to be way off when we talk about thyroid hormones. Humans appear to need much lower doses of exogenous thyroid hormones to see the same effects as rodents; and the dose regimen that delivered the most significant effect in the study at hand would translate to hilariously high doses of 3,5-T2 - doses you can luckily (?) never get out of any of the T2-supplements on the market).

Plus: The fact that a 2015 study by Pietzner et al. suggests that, in healthy euthyroid human beings, there's a J-shaped correlation of circulating 3,5-T2 levels and glucose (p >> 0.05 for insulin, waist, and subc. fat) with the latter being more or less constant until a certain optimal 3,5-T2 level is achieved and the fasting glucose levels "explode" (see Figure to the left).

After all, you can only hope for the 3,5-T2 the Brazilian scientists who have been dabbling with diiodothyronines in previous studies, already, to counter the ill effects of 3,3-diiodothyronine (3,3-T2).

Figure 2: (A) Fasting blood glucose, (B) glucose response during glucose tolerance test and (B) insulin levels in diet-induced obese mice according to treatment (da Silva Teixeira. 2016).

What's more, no supplement company can give you a guarantee that the 3,5-T3 in their products will fully counter the ill effects of 3,3-T2 on liver fat, the response to glucose tolerance tests, and the increased levels of insulin and appetite you can see in Figure 2 (and Figure 1, respectively) - no matter, how large the words "synergy" or "synergistically" are plastered all over the supplement bottle.

Read before using T2-products: "High-Dose 3,5-Diiodo-L-Thyronine (T2) Has Similar Side Effects as Regular Thyroid Hormones: Natural Thyroid Hormone Production ↓, Myocardial Stress ↑, Heart Weight ↑" | more.

So what's the verdict then: If you have understood that neither form of T2 is free of side effects (see "High-Dose 3,5-T2 Has Similar Sides as Regular Thyroid Hormones" | read it) and still want to use a T2-product, you better make sure it contains only the actually active 3,5-diiodothyronine (3,5-T2) and no 3,3-diiodothyronine) stupid supplement producers have put into the product to be able to claim that they would thus make sure to keep the side-effects at bay.

With a 3,5-T2 product you could at least hope for (a) weight loss / the prevention of weight gain, (b) fat loss and thus increases in relative lean mass, and, as the study at hand demonstrates (c) reduced liver fat and improved glucose tolerance and fasting glucose as well as insulin levels... all that, however, requires the product to be high-dosed - probably higher than the average fat burner you can buy at your favorite supplement shop (see red box for more information on the dosing regimen) | Comment!.

References:

• Pietzner, Maik, et al. "Translating pharmacological findings from hypothyroid rodents to euthyroid humans: is there a functional role of endogenous 3, 5-T2?." Thyroid 25.2 (2015): 188-197.

High Dose 3,5-Diiodo-L-Thyronine (T2) Has Similar Side Effects as Regular Thyroid Hormones: Natural Thyroid Hormone Production ↓, Myocardial Stress ↑, Heart Weight ↑

No, the rodents had "only" enlarged hearts, but hairloss is a common side effect of elevated thyroid hormones and could theoretically occur in the long run.

You have read about it on the SuppVersity and you've seen it as an ingredient in several recent fat burners... a purportedly 100% save non-suppressive thyroid hormone which goes by the name 3,5-Diiodo-L-Thyronine (T2).

While previous rodent studies highlighted only the beneficial metabolic effects, i.e. increases in fatty acid oxidation and resting energy expenditure, a recent study from the German Institute of Human Nutrition Potsdam-Rehbruecke raises serious concerns about what Wenke Jonas and her colleagues call the "indiscriminate administration of 3,5-T2 as powerful natural hormone for the treatment of hyperlipidemia and pandemic obesity" (Jonas. 2014) - in other words: About using T2 as a weight loss supplement or anti-obesity drug in lean or obese individuals without medical supervision.

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But what exactly is it, the scientists are concerned about? In their latest rodent study (there is as of now a scarcity of human studies on "T2") the German scientists observed dose-dependent thyromimetic effects of 3,5-T2 akin to those of T3 in diet-induced obese male C57BL/6J mice.

Figure 1: The study clearly indicates that the administration of T2 leads to highly significant reductions in serum T4 and serum T3 - one thing appears to be certain: T2 is not without side effects (data from Jonas. 2014)

That's in contrast to early studies which claimed that T2 had no thyromimetic effects on hypothalamus-pituitary-thyroid axis, but would act only peripherally to increase resting energy expenditure and fat oxidation, but in line with a rodent study by Padron et al. (2014) who reported only recently that Administration of 3,5-diiodothyronine (3,5-T2) causes central hypothyroidism and stimulates thyroid sensitive tissues of rats.

Maybe the dosage is just too high? Possible, but in view of the fact that the study reports a dose dependent increase in total energy expenditure that peaks at 14% with the high dose that was used in the study at hand, using less would be pointless anyways.

On the other hand, previous studies with only 300mcg of T2 per day showed no effect on T3 & T4 levels and a small but significant weight loss in two obese subjects with normal thyroid function (Antonelli. 2010). With N=2 the number of subject in this study from a (imho) non-peer-reviewed publication you cannot access online is yet far to low to call the results representative. Moreover, it is at least somewhat disturbing that all the beneficial research on T2 comes from Department of Internal Medicine at the University of Pisa, while other labs consistently find negative side effects.

As you can see in Figure 1, this claim is 100% unwarranted, the adminstration of 2.6µg/g body weight (since the standard calculations for human equivalent doses didn't work in previous studies on real thyroid hormones, I am not even attempting to give you the human equivalent) was not without consequences on the levels of the "classic" thyroid hormones T4 (thyroxine) and T3 (triiodothyronine) in the male C57BL/6J mice.

Figure 2: Despite the increase in energy expenditure the obese rodents didn't lose weight - they simply ate more.

Now, if the goal is to increase the fat oxidation and basal energy expenditure, this probably wouldn't matter, if you decide to stay "on" forever (if you don't you would to wait at least a couple of days for your natural thyroid production to kick in, again) and, more importantly, if these changes had nothing but beneficial consequences.

Unfortunately, Jonas et al. didn't just find that the hepatic thyroid target genes involved in lipid metabol were elevated to a similar extent as you would see it with T3, they did also find that the heart weight of the mice was significantly increased (just like you would see it with T3, again) after 28 days "on" T2.

And as if that wasn't bad enough, the increased appetite that's characteristic of the hyperthyroid state the rodents were in triggered an increase in food intake which rendered the increase in energy expenditure void and 12% increase in total energy expenditure void and kept the weight of the pre-fattened and thus obese mice stable.

In view of the latest results, I would actually have to rewrite all previous SuppVersity articles. I mean, I clearly wouldn't suggest it as a tool for lean bulking any longer.

Bottom line: As the scientists point out in their previously cited conclusion, the study at hand clearly "raise[s] concern about indiscriminate administration of 3,5-T2 as powerful natural hormone for the treatment of hyperlipidemia and pandemic obesity" (Jonas. 2014).

This does not mean that you cannot use T2 as a weight loss tool, but in fact of the previously mentioned absence of human data that would indicate that it does even work and considering the fact that the study at hand clearly indicates that it has similar same side effects as T3 (shut down of natural thyroid hormone production, increased heart weight indicative of myocardial stress) you could just as well use "real" thyroid hormones instead of 3,5-Diiodo-L-Thyronine (T2) if you are willing to live with the risk of side effects... or do you disagree? What are your thoughts and experiences? Let us know on the SuppVersity Facebook Page.

References:

• Antonelli, A., et al. "3, 5-diiodo-L-thyronine increases resting metabolic rate and reduces body weight without undesirable side effects." Journal of biological regulators and homeostatic agents 25.4 (2010): 655-660.
• Jonas, Wenke, et al. "3, 5-Diiodo-L-thyronine (3, 5-T2) exerts thyromimetic effects on hypothalamus-pituitary-thyroid axis, body composition, and energy metabolism in male dietinduced obese mice." Endocrinology (2014).
• Padron AS, Neto RAL, Pantaleão TU, de Souza Dos Santos MC, Araujo RL, de Andrade BM, da Silva Leandro M, de Castro JPSW, Ferreira ACF, de Carvalho DP. Administration of 3,5-diiodothyronine (3,5-T2) causes central hypothyroidism and stimulates thyroid sensitive tissues. J Endocrinol. 221.3 (2014):415–27

T2 a Fat Burner for Bulking? 3,5 Diiodo-L-Thyronine Wards Off Fat Gains & Doubles the Number of Hypertrophy-Prone Glycolytic Fast Twitch Muscle Fibers.

Image 1: T2-based fat burners work!
At least when interperitoneally
injected in overfed rats ;-)

Those of you, who followed my writings even in the pre-SuppVersity days may remember my Team-Andro review (original article in German, link is just a google translation) of the purported fat-loss effects of diiodo-L-tyronines. Almost two years ago, I concluded that scientific evidence for their use as "fat burners" in humans was non-existent, while the rodent data that was available at that point, only confirmed that high-dose supplemental 3,5 diiodo-thyronine (and to a lesser extent 3,3' diiodo-thyronine) was able to ameliorate the detrimental metabolic effects of hypothyrodism in rats. Now, the same group of Italian researchers who conducted the initial studies on the metabolic effects of these previously overlooked "by-products" (evidence suggest that they are in fact more than that) of thyroid hormone metabolism, came out with more recent - and certainly way more exciting results (Moreno. 2011).

To assess the effects of 3,5 diiodo-L-thyronine on non-hypothyroid, yet overfed animals, Maria Moreno and her colleagues fed three groups à 15 male Wistar rats (aged 8 weeks, body weight 300+/-5g) either a normal (measured by rat standards ;-) low fat or the infamous high-fat diet, scientists use to induce a pathology that is generally accepted as a model for human obesity and the metabolic syndrome.

Figure 1: Energy content and composition of control and high fat diet in kcal/g of body weight
(data adapted from Moreno. 2011)

Out of the two groups that were fed the hypercaloric high fat diet (cf. figure 1 for a comparison of macronutrient composition and energy content of the diets), one group was injected with 3,5 diiodoL-thyronine at a dose of 25µg/kg (human equivalent: 4µg/kg) interperitoneally. A procedure which turned did not only to reduce or even reverse the detrimental effects of high fat overfeeding on body weight, blood lipids and triglycerides of the animals, but also had direct effects on their muscle fiber composition and muscular glucose uptake via an increased expression of GLUT.4 transporters:

The HFD-induced increases in muscle levels of fatty acid translocase (3-fold; P<0.05) and TGs (2-fold, P<0.05) were prevented by T2 (each; P<0.05 vs. HFD). T2 increased insulin-stimulated Akt phosphorylation levels (~2.5-fold; P<0.05 vs.HFD). T2 induced these effects while sparing muscle mass and without cardiac hypertrophy [both side-effects commonly observed if the same effects are triggered by administration of T3]. T2 increased the muscle contents of fast/glycolytic fibers (2-fold; P<0.05 vs. HFD) and sarcolemmal glucose transporter 4 (3-fold; P<0.05 vs. HFD).

Unfortunately, from a dieters perspective, who will obviously be in a caloric deficit and does not want to ward fat gains off, but to get rid of his/her love-handles, these results are hardly significant. As it was the case in the previous studies by the same group, the model, the scientists used (hyperthyroid animals in previous studies; overfed animals in the study at hand) does not allow for a definitive conclusion on whether or not 3,5 diiodo-L-thyronine, let alone its short acting (cf. Lanni. 1994) "brother" 3,5,3' diiodo-L-thyronine, would facilitate fat loss in healthy (i.e. non-hypothyroid) human beings on a calorically restricted weight loss diet. That being said, the present data allows for the hypothesis that it could ameliorate the detrimental effects of caloric restriction on thyroidal determined parameters of basal metabolism and, at the same time, prevent muscle breakdown via the insulin-dependent upregulation of muscle protein synthesis by increased Akt phosphorylation.

Figure 2: Cholesterol, triglycerides and body weight after 8 weeks of high fat feeding in rats with and without T2 injections relative to values of normal-fed controls (data calculated based on Moreno. 2011)

On the other hand, the study clearly supports the notion that adding T2 to a bulk, i.e. a diet-phase which is intended to increase body, in most cases, muscle mass, could out turn out to be a good idea. The diet used in the study may be called "high fat diet", at the heart, it is however an overfeeding diet; and despite the different macronutrion composition this is not completely different from what body builders will do on a bulk. With appropriate doses (>320µg/day for a 80kg human being) and absorbtion (there is a major difference between interperitoneal injection and oral administration, taken with food, for example T2 could befall a similar fate as levothyroxin (T4) medications, which are to be taken hours away from your last meal to be absorbed properly) T2 could thus ...

• keep you lean due to its beneficial effects on energy expenditure in a state of nutrient overabundance
• help you build & restructure lean muscle via its effects on protein synthesis and muscle fiber type composition [note: a switch towards fast-twitch type-II muscle fibers will not only make you stronger, it will also help you

And since there were no changes observed in the serum levels of the main thyroid hormones T4 and T3, chances are, you could potentially get both these benefits without messing up with your natural thyroid production and without the risk of heart damage or muscle loss, which is a common side effect of using either T3 (both heart damage & muscle loss) or clenbuterol ("just" heart damage) for the exact same purposes, which is decreasing fat gain and increasing type-II to type-I muscle fiber ratio.

I-Force Dexaprine Ingredient Write-Up.

Figure 1: I-Force Nutrition's
newest fat burner Dexaprine

Just received an email from the marketing guys @I-Force Nutrition informing me that "Dexaprine is finally here...". Well, to be honest, I had not been waiting for it, but the email intrigued me and I would like to give you a brief rundown on the ingredients, which are "guaranteed to give you more energy, increased appetite suppression, and insane mood enhancement than you have ever experienced!" - I don't know about you, but I think I have heard similar claims before ;-)

Ok, here we go: One bottle of Dexaprine, which is 39.99 (pre-order offer @ I-Force webshop) has 60 servings (serving size 1 capsule) of the "thermogenic powerhouse" (I love these advertisment guys) @ 600mg of the following ingredients

• Thermophoric Amine Mood Enhancing Complex,
  which is basically just synephrine (from citrus aurantium) + geranamine (which is also known as 1,3-dimethylamylamine, 4-methyl-2-hexylamine, or as I-Force has it on the label 1,3-dimethylpentylamine)
  
• Extended Release Energy Complex,
  which is a combination of caffeine and theophylline, with the latter having identical beneficial (stimulant, beta receptor agonism, etc.) as well as detrimental (e.g. temporary insulin resistance in muscle tissue, cf. Colnes. 2010, adrenal problems due to long term (over-)use etc.) effects on perceived energy and weight loss, but a longer half-life, which is even prolonged by the concomittant admistration of caffeine (Jonkman. 1991)
  
• Anabolic Protein Synthesis Enhancing Complex,of which I think that it is completely mislabeled, because it is a combination of the two diiodo-L-Thyronines (also known as T2s), 3,3'-T2 and 3,5-T2, of which I have already written in a paper for a German BodyBuilding and fitness magazine (click here for Google-translation) that their impact on metabolic rate (in non-hypothyroid individuals) is probably negligible and would - according to the mice studies that are presently available - require much higher doses than those present in current "thyroid stimulating" products to up-regulate UCP significantly above "normal" levels.

So, overall this does leave us with a probably relatively long lasting stimulant that will enable you to work harder and thus burn more calories and subsequently more fat. Not bad, but nothing new or even revolutionary here.

On a side note: As it is quite often the case in the supplement industry, Dexaprine is deliberately named to sound similar to a potent drug, the synthetic amphetamine Dexedrine (has up to 15 mg dextro-Amphetamin per cap). This practice is about as shabby as calling a product XYZ-"drol". The latter, i.e. the "drols", have incidentally been banned by bodybuilding.com - good idea, guys ;-)