General Commentary ARTICLE
3-iodothryoanamine(T1AM): the missing link between amine oxidases and hyperglycemia?
- 1Università degli Studi di Firenze, Italy
Title of the original article”: 3-Iodothyronamine reduces insulin secretion in vitro via a mitochondrial mechanism. Lehmphul I, Hoefig CS, Köhrle published in J.Mol Cell Endocrinol. 2017 Jul 25. pii: S0303-7207(17)30399-4
Lehmphul et al. report the effect of 3-iodothyronamine in reducing insulin release in a model of immortalized pancreatic cells. Notwithstanding the simplified -cell model used, this article offers an opportunity to re-consider, possibly under a new light, an old issue of research which excited people working on amine oxidases in the last twenty years. Toward this aim, we would like to propose some points of reflection to the scientific community working on 3-iodothyronamine and thyroid hormone metabolites:
1. the paper indicates that 3-iodothyronamine reduces insulin release with a mechanism mediated, at least in part, by its oxidative metabolite, the 3-iodothyroacetic acid produced by mitochondrial monoamine oxidase (MAOs), type B (MAO-B) activity. This finding, confirming our observations and hypothesis on the role of 3-iodothyronamine as a source of active metabolites [1, 2], demonstrates for the first time that 3-iodothyronamine is a substrate for MAO-B, the MAO isoform in search of substrates and of functions;
2. the degradation of 3-iodothyronamine by MAO-B, with production of the corresponding aldehyde and hydrogen peroxide, potentially represents a self-standing mechanism independently of 3-iodothyronamine receptor activation on pancreatic cells.
Amine oxidases (AOs) are a heterogeneous class of enzymes including MAOs (type A and B) and semicarbazide-sensitive amine oxidases (SSAO). While MAOs are ubiquitous enzymes, being linked to the outer mitochondrial membrane (active site facing the cytoplasm), plasma membrane SSAO can have selective and species-specific tissue/cell expression. In addition, MAOs and SSAO are distinguishable by inhibitor sensitivity, substrate selectivity and affinity, subcellular localization. Noradrenaline and serotonin are among MAO-A substrates, dopamine and other trace amines including tyramine and -phenylethylamine are MAO-A, B and SSAO substrates. Up to now, direct evidence of 3-iodothyronamine is a substrate for MAO-A is lacking.
AOs catalysis: a pro-oxidant source for diabetes complications
The oxidative deamination carried out by AOs produces substrate-derived aldehydes, hydrogen peroxide, and ammonia. Aldehydes and hydrogen peroxide are well known pro-oxidant compounds scavenged by aldehyde dehydrogenase(s) and catalase activities, respectively, to the corresponding carboxylic acid and water. If produced outside cell by SSAO activity, hydrogen peroxide may have two fates: to enter cells or to remain outside cells. Both conditions can be a trigger for intra- or extracellular milieu oxidation with the latter compartmentalization as a pathogenic mechanistic event generating micro and macrovascular damage. Aldehydes from SSAO catalysis can generate carbonylation of extracellular proteins as their scavenging to the corresponding carboxylic acid can only occur intracellularly.
If produced by MAOs activities, hydrogen peroxide has limited freedom to diffuse and it may be subjected to catalase scavenging activity or pass throughout organelle membranes, generating a potential localized change in redox state. This condition is n recognized as one among the main pathogenic events triggering the pancreatic dysfunction, insulin resistance and long-term deleterious effects in exhausting cell/tissue antioxidant defenses. Furthermore, insulin-target cells were described as a preferential site for SSAO and MAOs expression [2, 3] with their activities further increased in hyperglycemia  as well as in hypertension, obesity and in other cardiovascular diseases [2--5], likely as a consequence of increased levels of pro-inflammatory signals .
AOs catalysis: the hypoglycemic and insulin mimetic effects of AOs substrates
Hydrogen peroxide can also have beneficial signaling activities, including its capacity to activate the trafficking of GLUT4 in adipocytes and other insulin-sensitive cells. Several studies have highlighted the use of high concentrations of not selective SSAO and MAOs substrates in stimulating GLUT4 activity, thus reducing hyperglycemia and mimicking insulin effects including adipocyte differentiation [7-,9]. On the other hand, SSAO substrate degradation was found a trigger for the generation of advanced glycation products . Therefore, whether AOs inhibitors or substrates should be proposed for controlling diabetes remained an open issue .
Protective effects of AOs inhibition: Clinical and experimental evidence
Aminoguanidine, an inhibitor of semicarbazide-sensitive amine oxidases is effective in reducing advanced glycation end products in diabetic patients and in experimental diabetes [12, 13] More interestingly, clinical and experimental evidence indicate that the beneficial effects of drug targeting angiotensin-II cascade in preventing diabetes complications might include the control of MAO activities [14,15], which may play a pathogenic role in different cardiomyopathies [5 ].
These evidence would confirm the pro-oxidant and pro-inflammatory role for amine oxidase catalysis and an overall beneficial effect of reducing their activities.
3-iodothyronamine : what’s new?
The novel fact is that 3-iodothyronamine i) is a common endogenous substrate for MAO-B and SSAO ii) plasma levels increased in diabetic patients  iii) administered to mice induce hyperglycemia with a mechanism which remains to be clarified (central and/or peripheral effect) but which is dependent, at least in part, on MAO activity [17,18]. To note, we have collected evidence demonstrating that MAO activity is involved in the conversion of endogenous but also pharmacological administered 3-iodothyronamine into 3-iodothyroacetic acid . This latter result suggests that AOs directly regulate tissue 3-iodothyroacetic acid/3-iodothyronamine Even if it is not demonstrated yet, at conditions of hyperglycemia, the products of 3-iodothyronamine oxidative deamination are expected to increase. Overall, hyperglycemia might reflect a condition of an unbalanced 3-iodothyronamine rate of synthesis and degradation, making available a great amount of the “pro-diabetic“ 3-iodothyroacetic acid and of pro-oxidant compounds which can exacerbate diabetes and its complications.
Since thyroid dysfunctions are a risk factor for diabetes and because 3-iodothyroacetic acid/3-iodothyronamine seems to be homeostatically regulated, the circle around amine oxidases and hyperglycemia might be conclusively closed. Consequently, the measure of 3-iodothyroacetic acid/3-iodothyronamine plasma levels may have diagnostic relevance to predict the risk of hyperglycemia .
Keywords: 3-iodothyronamine, 3-iodothyroacetic acid, Hyperglycemia, diabetes, Amine oxidases, amine oxidase inhibitors
Received: 12 Sep 2017;
Accepted: 09 Feb 2018.
Edited by:Alessandro Antonelli, University of Pisa, Italy
Reviewed by:Jean A. Boutin, Servier (France), France
Thomas Scanlan, Oregon Health & Science University, United States
Copyright: © 2018 Raimondi and Laurino. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Laura Raimondi, Università degli Studi di Firenze, Florence, Italy, firstname.lastname@example.org