Diiodothyronine

Diiodothyronine (3,5-T2): A Comprehensive Reference

1. Identity, Chemical Nature, and Common Forms

3,5-Diiodo-L-thyronine — abbreviated 3,5-T2 or simply T2 — is the compound most frequently designated by the common name "diiodothyronine" in the dietary supplement context. It is an endogenous metabolite of the classical thyroid hormones thyroxine (T4) and triiodothyronine (T3). The compound belongs to the iodothyronine family: it is a diphenyl ether amino acid bearing two iodine atoms at the 3 and 5 positions of the inner (tyrosyl) aromatic ring, with an unsubstituted outer ring. Its molecular formula is C₁₅H₁₃I₂NO₄; it is commercially catalogued under CAS number 1041-01-6 and available from biochemical suppliers as a research standard. It is described as an iodinated thyronine hormone that regulates gene activity affecting processes such as homeostasis, lipid metabolism, and insulin resistance.

Nomenclature note: The iodothyronine family produces several diiodothyronine isomers depending on which ring positions carry iodine. The three biologically recognized isomers are 3,5-T2 (inner ring, 3- and 5-positions), 3,3′-T2 (one atom on each ring, inner 3- and outer 3′-positions), and 3′,5′-T2 (outer ring). Two deiodinase enzymes, D1 and D3, can potentially catalyze the synthesis of these distinct diiodothyronines; until recent years, all T2 isomers were regarded as inactive metabolites of T3 and T4, because of their very low affinity for nuclear thyroid hormone receptors. Among these isomers, 3,5-T2 has attracted by far the most scientific attention as a biologically active molecule. Unless otherwise specified, all discussion below pertains to 3,5-T2.

Natural Occurrence and Endogenous Levels

3,5-Diiodothyronine occurs at low nanomolar concentrations in human serum, but might reach tissue concentrations similar to those of T4 and T3, at least based on data from rodent models. A population-based cross-sectional study (Study of Health in Pomerania) that measured 3,5-T2 by immunoassay in 761 euthyroid participants found a right-skewed distribution, with a median serum concentration of 0.24 nM (1st quartile: 0.20 nM; 3rd quartile: 0.37 nM). Rodent studies have estimated physiological serum concentrations to be around 1 ng/dl in men, with a daily production rate estimated to be around 1 μg.

Accurate quantification of circulating 3,5-T2 remains technically difficult. Immunoassay-based measurements in human sera reveal remarkable variations depending on the antibodies used in the assays and thus need to be interpreted with caution. Pilot analysis of human sera using LC-linear-ion-trap-mass-spectrometry yielded 3,5-T2 concentrations below the limit of quantification in the majority of cases, so the divergent results of both methods need to be reconciled by further studies.

Commercial Supplement Forms

Given the well-known metabolic effects of thyroid hormones, it is not surprising that T2 has found its way into the formulations of a number of dietary supplements that claim to decrease body fat; they are available over the counter. In supplement form, 3,5-T2 is typically supplied as encapsulated synthetic 3,5-diiodo-L-thyronine powder, often standardized to specific microgram doses per capsule. It has also appeared as an ingredient in multi-component weight-management and fat-burner preparations. One such historical product, LipoKinetix, contained diiodothyronine (described as a thyroid hormone metabolite called T2) alongside norephedrine, caffeine, yohimbine, and sodium usniate.

Formulations of natural desiccated thyroid such as Armour Thyroid contain some amount of T2 thyroid hormone; however, the dosing of T2 in natural desiccated thyroid is variable and is not felt to contribute significantly to the effectiveness of these medications.

2. Biosynthesis, Natural Sources, and Metabolic Origin

Thyroid hormones T4 and T3 play critical roles in differentiation, growth, and metabolism. 3,5-T2 arises from the sequential deiodination of these parent hormones by members of the deiodinase enzyme family. The postulated biosynthetic pathway proceeds from L-T4, the prohormone synthesized and secreted by the thyroid gland, through its 5′-deiodination product L-T3, which is generated in extrathyroidal tissues by the selenoenzyme 5-deiodinase type 1 or type 2. Indirect evidence, mainly from in vivo experiments in rodents, suggests that 3,5-T2 is then formed by a further 3′-deiodination reaction also catalyzed by one of these deiodinase enzymes.

3,5-T2 is synthesized from T3 via the deiodination pathway by Type III 5-deiodinase, occurring in peripheral tissues, mainly in the liver. In tissues, deiodinases can either activate or inactivate thyroid hormones: inactivation of thyroid hormones occurs by removal of an iodine atom on the inner ring, which converts the active triiodothyronine to diiodothyronine. Iodothyronine deiodinases are unusual in that these enzymes contain selenium, in the form of the otherwise rare amino acid selenocysteine.

Because 3,5-T2 is generated entirely through enzymatic metabolism of T4 and T3, it does not derive from any single botanical or food source. Its presence in animal-derived dietary materials (e.g., desiccated thyroid glandular preparations) reflects the normal iodothyronine profile of mammalian thyroid tissue.

3. Historical and Traditional Use

3,5-T2 as an isolated, chemically characterized entity has no documented history of traditional or ethnopharmacological use as such. It was not identified or named in pre-modern medicine, as its existence depends on modern endocrinology and organic chemistry.

The broader tradition in which 3,5-T2 participates is that of organotherapy — the therapeutic administration of animal gland extracts. In the late 19th and early 20th centuries, thyroid glandular extracts from pig and sheep thyroid glands were used medically to treat myxedema and goiter before synthetic hormones became available. The thyroid gland secretes thyroxine (T4), triiodothyronine (T3), and other iodothyronines, including reverse T3 and 3,3′-diiodothyronine, in proportions of approximately 80%, less than 20%, and less than 1%, respectively. Glandular extracts thus contained a spectrum of iodothyronines as naturally occurring components — including trace 3,5-T2 — but these minor constituents were neither identified nor credited with therapeutic effects at the time.

The modern supplement use of 3,5-T2 traces its origins to the bodybuilding and fitness communities of the late 1990s and early 2000s, where it began appearing in commercial "fat-burner" products based on extrapolations from early rodent research suggesting thyromimetic but non-thyrotoxic metabolic activity. In the context of its use in bodybuilder communities and the wellness scene (e.g., in products such as SAN T2 Xtreme Fat Burner), researchers have called for careful analysis of its mechanism of action and safety.

4. Key Constituents and Active Compounds

As a single, well-characterized small molecule rather than a botanical extract, 3,5-T2 does not contain "constituents" in the herbal sense. The active entity is the molecule itself: 3,5-diiodo-L-thyronine, a tyrosine-derived diphenyl ether amino acid with two iodine substituents. Its structural relationship to T3 and T4 gives it partial but distinct thyromimetic character.

Established Mechanisms of Action

Several lines of evidence suggest that 3,5-T2 mainly acts through thyroid hormone receptor (THR)-independent ways, with mitochondria as a likely cellular target; however, THR-mediated actions have also been described. The detailed cellular and molecular mechanisms through which 3,5-T2 elicits a multiplicity of actions remains unknown.

Mitochondrial actions: A growing number of researchers have focused on the possibility that T2 may actively regulate energy metabolism at the cellular, rather than the nuclear, level. Due to their biochemical features, mitochondria have been the focus of research on the thermogenic effects of thyroid hormones, and mitochondrial activities have been shown to be regulated both directly and indirectly by T2-specific pathways. Evidence indicates that 3,5-T2, a thyroid hormone derivative, exerts thermogenic effects by influencing mitochondrial activity in metabolically active tissues, such as liver, skeletal muscle, and brown adipose tissue (BAT).

SIRT1 / AMPK pathway: 3,5-T2 elicits the deacetylation of hepatic peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and sterol regulatory element binding protein-1c (SREBP-1c) through direct induction of SIRT1 activity, resulting in increased fatty acid oxidation and decreased lipogenesis. This non-genomic, sirtuin-dependent mechanism is among the most consistently reported molecular pathways for 3,5-T2's hypolipidemic effects in preclinical models.

Nuclear thyroid hormone receptor (THR) interactions: Recent studies in a fish model suggest that T2 can act as a ligand of the β-isoforms of the thyroid hormone receptor, which could explain effects on pituitary and liver, whose TH-dependent physiologies occur via that receptor isoform. However, cardiac hypertrophy observed at higher doses suggests that T2 can also engage the α1 receptor isoform, the most abundant in cardiac tissue.

Glucose metabolism: Hepatic mitochondria have been identified as specific targets of 3,5-T2; moreover, 3,5-T2 was suggested to influence glucose metabolism by stimulating glucose-6-phosphate dehydrogenase (G6PD) activity or by modulating gluconeogenesis via sirtuin 1.

Skeletal muscle: 3,5-T2 ameliorates muscle glucose uptake by increasing the response to insulin of Akt/PKB phosphorylation and induces structural and biochemical shifts toward glycolytic myofibers, thus enhancing muscle glycolytic capacity, producing metabolic benefits reminiscent of those induced by resistance exercise.

Brown adipose tissue: T2 activates thermogenesis, with UCP1 likely acting as the molecular determinant of this effect, and increases the sympathetic innervation and vascularization of BAT.

Oxygen consumption: Approximately 30 years ago, a seminal report showed that 3,5-T2 increased oxygen consumption more rapidly than T3 in hepatocytes. This rapid, non-genomic stimulation of hepatic oxygen consumption was among the earliest observations driving interest in 3,5-T2 as a distinct bioactive molecule.

5. Scientific Evidence by Area of Use

5.1 Energy Metabolism and Resting Metabolic Rate

Over 30 years of research has demonstrated that 3,5-T2, an endogenous metabolite of thyroid hormones, exhibits interesting metabolic activities. The preponderance of evidence, however, comes from preclinical (rodent and cell) models.

Rodent evidence: In rodent models, exogenously administered 3,5-T2 rapidly increases resting metabolic rate and elicits short-term beneficial hypolipidemic effects. Administration of 3,5-T2 to hypothyroid rodents rapidly stimulated their basal metabolic rate, prevented high-fat diet-induced obesity as well as steatosis, and increased oxidation of long-chain fatty acids.

Human evidence (extremely limited): Very few studies have evaluated the effects of endogenous and exogenous T2 in humans; further analyses on larger cohorts are needed to determine whether 3,5-T2 is a potent additional modulator of energy metabolism.

The primary human dataset consists of a single small uncontrolled study by Antonelli et al. (2011). Clinical results reported by Antonelli et al. upon a 4-week treatment at 300 µg/day in healthy volunteers showed that T2 decreased body weight and enhanced resting metabolic rate without affecting cardiac contractility. Antonelli et al. (2011) reported no changes in serum thyroid hormone levels in two euthyroid subjects treated for 3 weeks with a daily dose of 300 μg of 3,5-T2. As of the most recent systematic reviews, there is only one publication by Antonelli et al. that applied 3,5-T2 to humans, at a dosage by orders of magnitude lower than doses found to be effective in mouse models.

An additional human observation, referenced in the literature but described as uncontrolled, recorded that an uncontrolled study of 3,5-diiodothyronine administration to humans for 4 weeks by an unspecified route was associated with increased metabolic rate and reduced body weight.

Evidence strength: For resting metabolic rate and body weight effects in humans, evidence is confined to a single very small uncontrolled study (n = 2 in one report), with no randomized controlled trials published as of the most recent systematic literature. The rodent evidence is substantial but not directly translatable to human dosing or outcomes.

5.2 Obesity and Body Composition

Rodent evidence: Simultaneous 3,5-T2 administration (25 μg/100 g BW) for 4 weeks to rats feeding a high-fat diet prevents fatty liver and increases in body weight by increasing fatty acid oxidation rate and mitochondrial uncoupling to burn fat; reductions in serum triglycerides and cholesterol levels, as well as improved insulin sensitivity, are also associated with 3,5-T2 administration.

In an animal model using diet-induced obese male C57BL/6J mice, a high dose of T2 essentially mimicked all the physiological effects obtained with a T3 dose. These effects included suppression of the HPT axis, decreases in fat mass, serum leptin and cholesterol, and increases in lean mass, food intake, and hepatic expression of TH-dependent genes relevant to lipid metabolism.

A study in the gerbil Psammomys obesus (a spontaneous model of nutritional obesity and type 2 diabetes) found that after chronic administration of 3,5-T2, body weight was reduced by 23% and BMI by 32% (p < 0.001) compared to the untreated high-energy diet group; paradoxically, despite body weight loss, 3,5-T2 treatment increased calorie intake by 41%.

Conflicting preclinical data: Results are not uniformly positive across all rodent strains. In contrast with previous reports, in Sprague Dawley rats fed an unsaturated fat diet, T2 administration failed to improve NAFLD or whole body insulin sensitivity. The prior studies were performed in Wistar rats while this negative study was performed with Sprague Dawley rats, and differences in both lipoprotein metabolism and endocrine function have been noted between these two strains, suggesting that the effects of T2 on hepatic lipid metabolism may be influenced by specific diet conditions or limited to certain preclinical models.

Evidence strength: Preclinical evidence in rodents is substantial but internally inconsistent across strains and experimental conditions. Human evidence is absent for this specific endpoint beyond the single very small open-label study described above.

5.3 Dyslipidemia and Lipid Metabolism

Among natural metabolites, 3,5-diiodothyronine has been shown to powerfully reduce adiposity and dyslipidemia and to reverse hepatic steatosis in preclinical models without unfavorable side effects usually observed when T3 or T4 is used.

In a specific rodent model, 3,5-T2 (1.25 mg/100 g BW via daily gavage) reduces circulating total and LDL cholesterol as well as the liver level of apoB and circulating levels of both apoB48 and apoB100, but, at the same time, reduces plasma T4 levels in Western-type diet-fed low-density lipoprotein receptor-knockout mice. T2, by activating SIRT1, triggers a cascade of events resulting in improvement of the serum lipid profile, prevention of fat accumulation, and prevention of diet-induced insulin resistance.

Evidence strength: Preclinical only; no controlled human trials on lipid parameters have been published.

5.4 Non-Alcoholic Fatty Liver Disease (NAFLD) and Hepatic Steatosis

Recent studies suggest that 3,5-T2 is able to affect hepatic lipid metabolism, leading to a reduction in fat accumulation in the liver, a finding of significant importance in addressing non-alcoholic fatty liver disease. Administration of 3,5-T2 to HFD-obese Wistar rats was shown to reduce pre-existing hepatic fat accumulation through increased mitochondrial fatty acid oxidation coupled with less efficient utilization of substrates and reduced oxidative stress.

At the cellular and molecular level in fatty hepatocyte models, a proteomic study showed that 3,5-T2 counteracts several HFD-induced changes in the protein profile, mostly in the mitochondria; blue native-PAGE/in-gel activity analysis revealed that 3,5-T2 treatment results in stimulation of respiratory complexes, thus explaining, at least in part, the anti-steatosis effect.

Critically, however, this effect is not universally reproducible. Further study will be necessary before diiodothyronines can be considered an effective treatment for NAFLD and dyslipidemia.

Evidence strength: Predominantly preclinical (rodent, in vitro); the evidence base is mixed across different experimental models and no controlled human studies have been conducted specifically on hepatic steatosis endpoints.

5.5 Insulin Resistance and Glucose Metabolism

While T3 is usually considered the active form of thyroid hormone, 3,5-T2 exerts T3-like effects on energy consumption and lipid metabolism; 3,5-T2 also improves glucose tolerance in rats and 3,5-T2 levels correlate with fasting glucose in humans. In fact, 3,5-T2 treatment prevents diabetic nephropathy, hepatic steatosis induced by high-fat diet, insulin resistance, and weight gain during aging in Wistar male rats.

In diabetic Psammomys obesus, 3,5-T2 treatment reduced visceral adipose tissue, prevented insulin resistance, attenuated hyperglycemia and dyslipidemia, and reversed liver steatosis; it also decreased gluconeogenesis, increased ketogenesis, and enhanced respiration capacity.

Regarding the human epidemiological correlate, significant associations between 3,5-T2 and serum fasting glucose, thyrotropin (TSH), and leptin concentrations were detected (p < 0.05) in the Study of Health in Pomerania; however, age, sex, smoking, and blood lipid profile parameters did not show significant associations with circulating 3,5-T2. Associations in a cross-sectional study do not establish causality or indicate that supplementation is effective.

Evidence strength: Preclinical evidence from multiple rodent models is suggestive; one epidemiological cross-sectional association exists in humans. No randomized controlled trials addressing insulin resistance or glycemia in humans have been published.

5.6 Thermogenesis and Brown Adipose Tissue

Evidence indicates that 3,5-T2, a thyroid hormone derivative, exerts thermogenic effects by influencing mitochondrial activity in metabolically active tissues, such as liver, skeletal muscle, and BAT. At lower doses in high-fat diet-fed rats, at doses of 25 μg 3,5-T2/100 g BW for 4 weeks, no signs of suppression of the hypothalamus-pituitary-thyroid (HPT) axis and cardiac hypertrophy are detected.

Evidence strength: Rodent and in vitro only; no human thermogenesis trials have been conducted.

5.7 Cardiac Metabolism

Chronic administration of a low T2 dosage to two healthy volunteers increased resting metabolic rate and decreased body weight by inducing a reduction in steatosis and in the total serum cholesterol levels, without affecting cardiac function. In rodent studies at higher doses, a higher dosage (2.5 µg/g) of T2 administration was reported to exert thyromimetic effects, since it induced cardiac hypertrophy and an overall genomic effect similar to that produced by T3. However, the cardiac effects of T2 have not been extensively investigated so far.

Evidence strength: Very limited human data; dose-dependent concerns in animals. No controlled human cardiac endpoint studies exist.

6. Body Systems and Health Areas Associated with 3,5-T2

• Endocrine / Thyroid axis: 3,5-T2 is intrinsically part of the thyroid hormone metabolome. It can interact with thyroid hormone receptors and with the hypothalamus-pituitary-thyroid (HPT) feedback axis, with dose-dependent TSH suppression documented in multiple animal studies.
• Metabolic / Energy expenditure: Directly implicated in resting metabolic rate, mitochondrial respiration, and substrate oxidation in liver, skeletal muscle, and BAT.
• Hepatic: Studied extensively for anti-steatotic effects; affects hepatic fatty acid oxidation, lipogenesis, and cholesterol metabolism.
• Lipid metabolism: Preclinical data show reductions in serum triglycerides, total cholesterol, LDL, and apolipoprotein B fractions.
• Glucose metabolism / Insulin sensitivity: Preclinical evidence for improved insulin sensitivity in skeletal muscle and liver; epidemiological association with fasting glucose in humans.
• Cardiac: Appears to affect cardiac energy substrate utilization; at higher doses in rodents, cardiac hypertrophy has been observed.
• Brown adipose tissue: Evidence for activation of thermogenic programming and UCP1 expression.
• Skeletal muscle: Evidence for shifts toward glycolytic fiber phenotypes and improved insulin-stimulated glucose uptake.

7. Dosage Forms and Dosages Reported in Studies

The following dosages are reported directly from identified sources and are provided for informational accuracy only:

• Human pilot study (Antonelli et al., 2011): Two euthyroid subjects treated for 3 weeks with a daily dose of 300 μg of 3,5-T2; no changes in serum thyroid hormone levels were reported at this dose.
• Human healthy volunteers (Antonelli et al., extended follow-up): 300 µg/day for 4 weeks; decreased body weight and enhanced resting metabolic rate were reported without affecting cardiac contractility.
• Rodent high-fat diet model: 25 μg/100 g body weight per day for 4 weeks, administered simultaneously with high-fat diet, prevented fatty liver and body weight increases.
• Diet-induced obese mice: 250 μg/100 g BW per day for 14 or 28 days (intraperitoneal), showing beneficial effects on adiposity, serum leptin, and energy expenditure.
• Chow-fed rats (chronic aging study): Subcutaneous injection at 25, 50, or 75 μg/100 g BW for 90 days; significantly reduced body mass and improved glucose tolerance, with heart rate and mass remaining unchanged; TSH levels remained normal at the 25 μg/100 g BW dose but were slightly lowered at 50 and 75 μg/100 g BW doses.
• Gerbil diabetes model: 3,5-T2 tested at 25 µg dose, administered as a subcutaneous pellet implant for 10 weeks; isolated hepatocytes were incubated at 10⁻⁶ M and 10⁻⁹ M.
• Obese mouse model (higher dose): 2.5 μg/g body weight; at this dose, T3-like changes in hepatic gene expression and increased type I deiodinase activity were observed.

No standardized or regulatory-approved dosing protocol exists for human supplementation with 3,5-T2 as of the available literature.

8. Safety Considerations and Interactions

8.1 Hypothalamus-Pituitary-Thyroid (HPT) Axis Suppression

The most consistently documented and scientifically significant safety concern with exogenous 3,5-T2 is dose-dependent suppression of the HPT axis. The current literature indicates that, in addition to increased metabolism and reduced fat mass, T2 administration also leads to suppression of the HPT axis, increased food intake, and cardiac hypertrophy. A particular point of concern is the observation that the lower dose of T2 used in mouse studies exerts negligible effects on adiposity and metabolic outcomes, yet results in a marked suppression of the HPT axis leading to reduced levels of circulating T4 and T3 (and presumably TSH), with unknown long-term consequences.

Serum TSH, T3, and T4 were reduced in a 3,5-T2 dose-dependent manner in rodents, whereas oxygen consumption increased in these animals, indicating the direct action of 3,5-T2 on this physiological variable. Thus, 3,5-T2 acts as a direct stimulator of energy expenditure and reduces body mass gain; however, TSH suppression may develop secondary to 3,5-T2 administration.

8.2 Cardiac Effects

Data from obese mouse studies imply the risk of significant adverse interference with the HPT axis as well as cardiac and hepatic side effects with pharmacological use of 3,5-T2. Enlarged heart weights in treated mice indicate potential cardiac side effects of 3,5-T2 beyond hepatic thyromimetic actions. These cardiac effects appear to be dose-dependent, with lower doses in some studies not causing hypertrophy, while the dose-response relationship in humans is unknown.

8.3 Thyromimetic Effects at Higher Doses

Experiments in diet-induced obese male C57BL/6J mice revealed dose-dependent thyromimetic effects of 3,5-T2 akin to those of T3; 3,5-T2 treatment exerted a negative feedback regulation on the HPT axis, similar to T3. Therefore, clinical long-term use of the endogenous TH metabolite 3,5-T2 as an antihyperlipidemic drug similar to TRβ-selective synthetic ligands without risk of producing T3-like adverse effects might not be realistic.

8.4 Hepatic Effects

Lean and diet-induced obese male mice treated for 4 weeks with a 3,5-T2 dose of 2.5 μg/g BW show an altered expression of genes encoding hepatic xenobiotic-metabolizing enzymes involved in catabolism and inactivation of xenobiotics and thyroid hormones as well as in hepatic steroid and lipid metabolism; hence, the administration of this high dose of 3,5-T2 might exert adverse hepatic effects.

8.5 Interference with Clinical Thyroid Function Testing

A clinically important consideration in the supplement context is that self-administration of 3,5-T2 may confound clinical laboratory interpretation. 3,5-T2 escapes regular detection by commercially available clinical routine assays used for thyroid function tests, which may be seriously disrupted in individuals self-administering 3,5-T2 obtained over the counter or from other sources. This means that individuals using T2 supplements while under thyroid monitoring could have meaningfully altered thyroid physiology (HPT axis suppression, altered T4/T3 levels) that would not be reflected by routine TSH or free hormone assays, potentially leading to misdiagnosis or mistreatment.

8.6 Regulatory and Research Community Warnings

Although positive anti-steatotic effects have been observed in rodent models, use of 3,5-T2 as a muscle anabolic, slimming, or fitness drug, easily obtained without medical prescription, must be advised against, considering its potency in suppressing the HPT axis and causing adverse cardiac side effects.

8.7 Interaction with Endogenous Thyroid Hormone Levels and Medications

Because 3,5-T2 acts on the same regulatory axis as thyroid hormones T3 and T4, interactions with levothyroxine (synthetic T4), liothyronine (synthetic T3), and natural desiccated thyroid medications are biologically plausible through shared HPT axis feedback mechanisms and competitive binding at deiodinase enzymes and thyroid hormone receptors. However, specific pharmacokinetic drug interaction studies in humans have not been published as of available literature.

8.8 Elevated 3,5-T2 Levels in Disease States

Elevated endogenous 3,5-T2 serum concentrations have been observed as associations (not established causal relationships) in certain clinical conditions. Elevated 3,5-T2 serum concentrations were found in several situations including impaired renal function, chronic dialysis, sepsis, non-survival in the ICU, as well as post-operative atrial fibrillation in studies using a monoclonal antibody-based chemiluminescence immunoassay. These associations do not indicate that supplemental 3,5-T2 causes these conditions but rather that its physiological regulation is disrupted in systemic illness.

8.9 Overall Evidence Summary for Safety

The safety profile of exogenous 3,5-T2 in humans is, at present, incompletely characterized due to the very limited clinical data. The only published controlled human exposure involves a very small number of subjects at one dose level over a short duration. The preclinical data raise dose-dependent concerns regarding HPT axis suppression (even at sub-metabolically-effective doses), cardiac hypertrophy (at higher doses), and hepatic enzyme alterations. The favorable safety signals reported in some rodent studies (no HPT axis effects at 25 μg/100 g BW for 4 weeks) have not been reproduced across all experimental conditions, and translate poorly to human equivalent dosing without additional data.

References

• Senese R, de Lange P, Petito G, Moreno M, Goglia F, Lanni A. 3,5-Diiodothyronine: A Novel Thyroid Hormone Metabolite and Potent Modulator of Energy Metabolism. Front Endocrinol. 2018;9:427. PMC6068267
• Hernandez A. 3,5-Diiodo-L-Thyronine (T2) in Dietary Supplements: What Are the Physiological Effects? Endocrinology. 2015;156(2):386–388. PMC4272398
• Jonas W, Lietzow J, Wohlgemuth F, et al. 3,5-Diiodo-L-Thyronine (3,5-T2) Exerts Thyromimetic Effects on HPT Axis, Body Composition, and Energy Metabolism in Male Diet-Induced Obese Mice. Endocrinology. 2015;156(2):389–399. PMC4272399
• Müller P, et al. Translating Pharmacological Findings from Hypothyroid Rodents to Euthyroid Humans: Is There a Functional Role of Endogenous 3,5-T2? Thyroid. 2015. PMC4322092
• Dietrich JW, et al. 3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action. Front Endocrinol. 2019;10:787. PMC6960127
• Vatner DF, et al. 3,5 Diiodo-L-Thyronine (T2) Does Not Prevent Hepatic Steatosis or Insulin Resistance in Fat-Fed Sprague Dawley Rats. PLoS ONE. 2015;10:e0140837. PMC4618341
• de Lange P, et al. Nonthyrotoxic Prevention of Diet-Induced Insulin Resistance by 3,5-Diiodo-L-Thyronine in Rats. Diabetes. 2011;60:2730–2739. PMC3198093
• Hammoudi N, et al. Potential Applications of Thyroid Hormone Derivatives in Obesity and Type 2 Diabetes: Focus on 3,5-Diiodothyronine in Psammomys obesus. Front Endocrinol. 2022. PMC9329750
• Lanni A, et al. 3,5-Diiodo-l-Thyronine Increases Glucose Consumption in Cardiomyoblasts Without Affecting the Contractile Performance in Rat Heart. Front Endocrinol. 2018;9:282. PMC5988897
• Lorenzini L, et al. Assay of Endogenous 3,5-diiodo-L-thyronine and 3,3′-diiodo-L-thyronine in Human Serum: A Feasibility Study. Front Endocrinol. 2019;10:88.
• Cioffi F, et al. Effect of Iodothyronines on Thermogenesis: Focus on Brown Adipose Tissue. Front Endocrinol. 2018;9:254.
• Moreno M, et al. Similarities and Differences in the Peripheral Actions of Thyroid Hormones and Their Metabolites. Front Endocrinol. 2018;9:394.
• Jonas W, et al. 3,5-Diiodothyronine (3,5-T2) reduces blood glucose independently of insulin sensitization in obese mice. PubMed. 2016.
• Bianco AC, et al. Role of the Iodothyronine Deiodinases in the Physiology and Pathophysiology of Thyroid Hormone Action. Endocr Rev. 2002. PMC3673746
• Padron AS, et al. Administration of 3,5-diiodothyronine (3,5-T2) causes central hypothyroidism and stimulates thyroid-sensitive tissues. J Endocrinol. 2014;221:415–427.
• Silvestri E, et al. Models of Non-Alcoholic Fatty Liver Disease and Potential Translational Value: the Effects of 3,5-L-diiodothyronine. PubMed. 2017.
• Müller P, et al. A Thyroid Hormone-Independent Molecular Fingerprint of 3,5-Diiodothyronine Suggests a Strong Relationship with Coffee Metabolism in Humans. Front Endocrinol. 2019. PMC6918876
• Comparative effects of 3,5-diiodo-L-thyronine and T3 on mitochondrial damage and cGAS/STING-driven inflammation in liver of hypothyroid rats. Front Endocrinol. 2024. PMC11410700
• ScienceDirect Topics: Diiodothyronine — overview.