Research Review: 3,5-diiodothyronine (3,5-T2) and Metabolism

At least 13 million Americans have some form of thyroid disorders--more than 80% of these are attributable to an under-active thyroid gland — hypothyroidism. The condition is more common in women, and the rate rises with age, reaching 20% in women over 65 [Harvard Health Publications].

From Wikipedia, here is a brief overview of thyroid function:

The thyroid gland is an endocrine gland in the neck, and consists of two lobes connected by an isthmus. It is found at the front of the neck, below the Adam's apple. The thyroid gland secretes thyroid hormones, which primarily influence the metabolic rate and protein synthesis. The hormones also have many other effects including those on development. The thyroid hormones T₃ and T₄ are synthesized from iodine and tyrosine. The thyroid also produces the hormone calcitonin, which plays a role in calcium homeostasis.^[1]

Hormonal output from the thyroid is regulated by thyroid-stimulating hormone (TSH) secreted from the anterior pituitary, which itself is regulated by thyrotropin-releasing hormone (TRH) produced by the hypothalamus.^[2]

The thyroid may be affected by several diseases. Hyperthyroidism occurs when the gland produces excessive amounts of thyroid hormones, the most common cause being Graves' disease—an autoimmune disorder. In contrast, hypothyroidism is a state of insufficient thyroid hormone production. Worldwide, the most common cause is iodine deficiency. Thyroid hormones are important for development, and hypothyroidism secondary to iodine deficiency remains the leading cause of preventable intellectual disability.^[3] In iodine-sufficient regions, the most common cause of hypothyroidism is Hashimoto's thyroiditis—also an autoimmune disease. In addition, the thyroid gland may also develop several types of nodules and cancer.

Thyroid hormones are important throughout the body, acting to increase the basal metabolic rate and protein synthesis, assist in regulating long bone growth (with growth hormone), and increase the body's sensitivity to catecholamines (such as adrenaline). Thyroid hormones regulate protein, fat, and carbohydrate metabolism, stimulate vitamin metabolism, and decrease LDL cholesterol levels. As many people diagnosed with hypothyroidism can attest, thyroid hormone impact heat generation in humans (cold hands and feet are symptomatic of low thyroid levels).

The symptoms of hypothyroidism are variable and may include fatigue, sluggishness, cold intolerance, weight gain, constipation, muscle or joint pain, thin and brittle hair or fingernails, reduced sexual drive, high blood pressure, high cholesterol, slow heart rate, problems with concentration and memory, and depression.

In fact, if you go to your psychiatrist or family doctor with concerns about depression, before accepting any antidepressant medications, request a thyroid panel (total T₄ (thyroxine), free T₄, total T₃ (triiodothyronine), free T₃, and TSH). Most tests will only look at totals of T₃, T₄, and TSH, which can be very misleading. Only free (unbound) T₃ is functionally biologically active (3- to 5-fold more active than T₄).

Thyroxine (T₄) is the prohormone to triiodothyronine (T₃), both of which are tyrosine-based hormones and partially composed of iodine (see molecular model). In fact, most cases of hypothyroidism can be linked to low iodine levels.

        
triiodothyronine (T₃)                             thyroxine (T₄)

Treating Low Thyroid

Unless you are medically shown to have low thyroid levels that require pharmaceutical intervention, your best bet is to start with natural supplementation with l-tyrosine (an amino acid) and iodine (sea kelp is often the best choice as some iodine supplements are dosed too high and make hypothyroidism worse).

Jill Grunewald, who was diagnosed with Hashimoto's disease and is in remission solely through nutritional interventions, offers the following advise, condensed to bullet points - [I've added some comments in brackets].

1. Just say no to the dietary bungee cord (reduce or eliminate caffeine and sugar, including refined carbohydrates like flour, which the body treats like sugar, and grains).

2. Up the protein. Protein transports thyroid hormone to all your tissues and enjoying it at each meal can help normalize thyroid function. [My Note: Not soy, which is known to disrupt thyroid function.]

3. Get fat. Healthy fats are your friends--if you’re getting insufficient fat and cholesterol, you could be exacerbating hormonal imbalance, which includes thyroid hormones. 

4. Nutrient-up. Not having enough of these micronutrients and minerals can aggravate symptoms: vitamin D, iron, omega-3 fatty acids, selenium, zinc, copper, vitamin A, the B vitamins, and iodine.

• Optimal vitamin D levels are between 50-80 ng/mL; anything below 32 contributes to hormone pathway disruption.
• Omega-3s, found in fish, grass-fed animal products, flaxseeds, and walnuts, are the building blocks for hormones that control immune function and cell growth, are critical to thyroid function, and improve the ability to respond to thyroid hormones. 

[My notes: Men should take a fish oil product higher in DHA than EPA, while women and older adults tend to benefit more from higher EPA. Be care with vitamin D, which is fat soluble and can build up in tissues for some people (1000-2000 iu daily). Selenium can be more harmful than helpful, especially in men. No iron for men, or for post-menopausal women, unless anemic. Supplemental zinc should be dosed low, 30 mg or less (especially in men, where dosing above 100 mg/day or for longer than 10 years can increase prostate cancer risk).]

5. Go 100% gluten-free. For those with Hashimoto’s, eating gluten can increase the autoimmune attack on your thyroid.

6. Be mindful of goitrogens (foods that can interfere with thyroid function), including broccoli, Brussels sprouts, cabbage, cauliflower, kale, kohlrabi, rutabaga, turnips, millet, spinach, strawberries, peaches, watercress, peanuts, radishes, and soybeans.

7. Go for the glutathione. Glutathione can boost your body’s ability to modulate and regulate the immune system, dampen autoimmune flare-ups, and protect and heal thyroid tissue.

8. Address underlying food sensitivities. [My advise: Look into an anti-inflammatory diet.]

9. Do a gut check. [My note: The microbiome is the key to health and may play a central role in Hashimoto's.]

10. Address silent inflammation with whole foods nutrition. Systemic inflammation and autoimmunity often go hand-in-hand. [See #8.]

11. Address adrenal fatigue. It’s uncommon to have hypothyroidism without some level of adrenal fatigue.

12. Look at your stress and practice relaxation. The thyroid is a very sensitive gland and is exceptionally reactive to the stress response.

13. Ask for the thyroid collar. Next time you're getting an x-ray at the dentist, ask for the thyroid collar.

When pharmaceutical intervention is required, there are only two medically accepted options, or less frequently, a combination of the two. This is from T-Nation's The Thyroid Handbook.

Synthroid: L-thyroxine (T₄)

This drug is normally used as a replacement therapy in congenital or acquired hypothyroidism and it's also used to suppress TSH in cases where a person is suffering from hyperthyroidism. It's released in a 20/1 ratio in respect to T₃. T₄ is less potent than T₃, metabolically speaking, and has a half life of six to seven days in euthyroid humans. (That's where a person's thyroid gland is enlarged but it's not associated with inflammation or cancer. Also called goiter.)

Cytomel: L-triiodothyronine (T₃)

This drug is also used to treat hypothyroidism and is even used to determine if someone has hyperthyroidism. It's said to be three to five times more metabolically potent than T₄ and has a half-life of approximately 2.5 days. The usual dosages used to treat hypothyroidism are 5 to 25 mcg daily and gradually increasing the dosage to 60 to 75 mcg daily. Some people need as much as 100 mcg daily – 20 to 25 mcg of T₃ is approximately the same as 100 mcg of T₄.

Bodybuilders have been using these drugs for decades to boost metabolism and shed fat. However, both of these drugs (Cytomel especially) can down-regulate normal thyroid function in the same ways that exogenous androgen can down-regulate normal testosterone production.

Still, these drugs are used to offset the reduced metabolism that occurs in carbohydrate restriction. Depending on one's own physiology, it takes anywhere from 50 to 120 grams of carb intake daily to prevent T₃ decline during low-carb dieting.



Enter 3,5-diiodothyronine (3,5-T₂)

T₃ is essentially deiodination of a T₄ molecule (via iodothyronine deiodinase type I, II, and III), and T₂ is deiodination of a T₃ molecule.

There are two T₂ hormones: 3,5-diiodothyronine and 3,3-diiodothyronine. Both of them are metabolites of T₃ and T₄, but they exhibit very different physiological actions.

T₃ and 3,5-T₂ both reduce body weight, adiposity and [increase] body temperature despite increased food intake. 3,3-T₂ lacks these effects. T₃ and 3,5-T₂ reduce blood glucose levels, whereas 3,3-T₂ worsens glucose tolerance. Neither T₃ nor 3,5-T2 affects markers of insulin sensitization in skeletal muscle or white adipose tissue (WAT), but both reduce hepatic GLUT2 glucose transporter levels and glucose output. T₃ and 3,5-T₂ also induce expression of mitochondrial uncoupling proteins (UCPs) 3 and 1 in skeletal muscle and WAT respectively. [Da Silva Teixeira, et al, Acta Physiol 2016]

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

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 ... increase the amount of liver fat and food intake.

Considerable research supports 3,5-T₂, which has been shown to possess the following attributes (references for these stats are found below):

• increase hepatic oxygen consumption by about 30%
• act rapidly and directly through activation of the mitochondria
• shows a dose-dependent effect which increased RM and oxidative capacity (greatest response to T₂ was in liver and in brown adipose tissue [BAT], the kind that burns fat)
• T₂ was also shown to have a similar effect to that of T₃ on lipid metabolism with T₂ actually doing a little better in some tissue

Thyroid stimulating hormone (TSH) inhibition is not as severe or as last with 3,5-T₂ vs. T₃:

• TSH inhibition isn't nearly as severe with T₂ as it is with T₃; T₂ is 13% less inhibitory on TSH levels, as compared to T₃
• T₃ and T₂ suppressed TSH to similar levels--it took 15 mcg/100g body weight per day of T₃ to accomplish this, while it took 200 mcg/100g body weight per day of T₂ to accomplish the same thing (it took about 13 times more T₂ to exert the same effect on TSH as T₃)

Bottom Line

3,5-T₂ can:

• reduce body weight and adiposity (fat storage)n despite increased food intake
• reduce blood glucose levels
• reduce hepatic GLUT2 glucose transporter levels and glucose output
• increase body temperature
• induce expression of mitochondrial uncoupling proteins in skeletal muscle (UCP3) and WAT/BAT (UCP1)--UCPs are crucial for fat burning
• increase hepatic oxygen consumption by about 30%
• act rapidly and directly through activation of the mitochondria

3,3-T₂ can:

• impair glucose metabolism
• worsen glucose tolerance
• increase the amount of liver fat and food intake
• not decrease body weight or adiposity

Most doctors are ignorant of the benefits of T₂, despite decades of research. However, there are OTC supplements available that contain this hormone, although most contain both 3,5-T₂ and 3,3-T₂. The only product I have found that favors 3,5-T₂ over 3,3-T₂ is ThyroTwin (175 mcg 3,5-T₂, 25 mcg 3,3-T₂ per capsule).

If you choose to supplement with 3,5-T₂, be sure to maintain adequate protein intake (1.0-1.5 grams per pound of body weight), do weight training 3-4 times a week (preferably full-body workouts), and if you choose to do so, or want to do so, add low-dose testosterone therapy to offset potential muscle loss (inject subcutaneously for better results).

3,5-T₂ is an effective metabolism booster, fat burner, and it may be useful in treating Hashimoto's without resorting to the stronger and possibly more catabolic T₃.

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Here are a handful of recent articles on 3,5-T₂ (with links):

da Silva Teixeira, S., Filgueira, C., Sieglaff, D. H., Benod, C., Villagomez, R., Minze, L. J., Zhang, A., Webb, P. and Nunes, M. T. (2016), 3,5-diiodothyronine (3,5-T2) reduces blood glucose independently of insulin sensitization in obese mice. Acta Physiologica. doi: 10.1111/apha.12821

Lombardi A, Moreno M, de Lange P, Iossa S, Busiello RA, Goglia F. Regulation of skeletal muscle mitochondrial activity by thyroid hormones: focus on the “old” triiodothyronine and the “emerging” 3,5-diiodothyronine. Frontiers in Physiology. 2015;6:237. doi:10.3389/fphys.2015.00237.

Pietzner M, Lehmphul I, Friedrich N, et al. Translating Pharmacological Findings from Hypothyroid Rodents to Euthyroid Humans: Is There a Functional Role of Endogenous 3,5-T2? Thyroid. 2015;25(2):188-197. doi:10.1089/thy.2014.0262.

Goglia F. The effects of 3,5-diiodothyronine on energy balance. Frontiers in Physiology. 2014;5:528. doi:10.3389/fphys.2014.00528.

Padron AS, Neto RAL, Pantaleão TU, et al. Administration of 3,5-diiodothyronine (3,5-T2) causes central hypothyroidism and stimulates thyroid-sensitive tissues. The Journal of Endocrinology. 2014;221(3):415-427. doi:10.1530/JOE-13-0502.

A. Lombardi, P. de Lange, E. Silvestri, R. A. Busiello, A. Lanni, F. Goglia, M. Moreno. 3,5-Diiodo-l-thyronine rapidly enhances mitochondrial fatty acid oxidation rate and thermogenesis in rat skeletal muscle: AMP-activated protein kinase involvement. American Journal of Physiology - Endocrinology and MetabolismPublished 1 March 2009 Vol. 296 no. 3, E497-E502 DOI:10.1152/ajpendo.90642.2008
Goglia F. Biological Effects of 3,5-Diiodothyronine (T2). Biochemistry (Moscow), 70(2), 2005: 164-172. Translated from Biokhimiya, 70(2), 2005: 203-213.

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References for 3,5-T₂ and 3,5-T₂ vs. T₃ (via T-Nation):

• Horst C, et al. "Rapid stimulation of hepatic oxygen consumption by 3,5-di-iodo-L-thyronine." Biochem J 1989 Aug 1;261(3):945-50
• Lanni A, et al. "Calorigenic effect of diiodothyronines in the rat." J Physiol 1996 Aug 1;494 (Pt 3):831-7
• Goglia F, et al. "Action of thyroid hormones at the cellular level: the mitochondrial target." FEBS Lett 1999 Jun 11;452(3):115-20
• Lanni A, et al. "Effect of 3,3'-diiodothyronine and 3,5-diiodothyronine on rat liver oxidative capacity." Molecular and Cellular Endocrinology. Volume 86, Issue 3. 1992
• Lanni A, et al. J. Endocrinol. 136:59-64 1993.
• O'Reilly I, Murphy MP. Acta Endocrinol. 127:542-546 1992.
• Lanni A, et al. "3,5-Diiodo-L-thyronine and 3,5,3'-triiodo-L-thyronine both improve the cold tolerance of hypothyroid rats, but possibly via different mechanisms." Pflugers Arch 1998 Aug;436(3):407-14
• Varghese S, Oommen OV. "Thyroid hormones regulate lipid metabolism in a teleost Anabas testudineus (Bloch)." Comp Biochem Physiol B Biochem Mol Biol 1999 Dec;124(4):445-50
• J. Kvetny. Horm. Metab. Res. 24:322-325, 1992.
• Moreno M, et al. "Effect of 3,5-Diiodo-L-thyronine on thyroid stimulating hormone and growth hormone serum levels in hypothyroid rats." Life Sciences, Volume 62, No.26, pp. 2369-2377, 1998.
• Horst C, et al. "3,5-Di-iodo-L-thyronine suppresses TSH in rats in vivo and in rat pituitary fragments in vitro." J Endocrinol 1995 May;145(2):291-7