Thyroid hormones in diabetes, cancer, and aging

Aging Cell. 2020;19:e13260.   | 1 of 25 https://doi.org/10.1111/acel.13260 wileyonlinelibrary.com/journal/acel 1 | INTRODUCTION Thyroid hormone (TH) production is a tightly regulated process controlled by a classic negative feedback loop involving the hypothalamus, the pituitary, and the thyroid, which has led to the common name hypothalamus–pituitary–thyroid axis (Figure 1). The thyrotropin-releasing hormone (TRH) is produced in the hypothalamus. Once released, TRH reaches the pituitary gland and binds to the TRH receptor and stimulates the production and secretion of thyroid-stimulating hormone (TSH), also known as thyrotropin (Liu et al., 2019). In the thyroid, TSH binds to the TSH receptor (TSHR) and induces TH production. When needed, Received:24April2020 | Revised:27July2020 | Accepted:13September2020 DOI: 10.1111/acel.13260 REVIEW Thyroid hormones in diabetes, cancer, and aging Benoit R. Gauthier1,2 | Alejandro Sola-García1 | María Ángeles Cáliz-Molina1 | Petra Isabel Lorenzo1 | Nadia Cobo-Vuilleumier1 | Vivian Capilla-González1 | Alejandro Martin-Montalvo1 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Aging CellpublishedbytheAnatomicalSocietyandJohnWiley&SonsLtd. 1Department of Cell Therapy and Regeneration, Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER,JuntadeAndalucíaUniversity of Pablo de Olavide-University of Seville-CSIC, Seville, Spain 2Biomedical Research Network on Diabetes and Related Metabolic DiseasesCIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Correspondence Alejandro Martin-Montalvo, Department of Cell Therapy and Regeneration, Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, JuntadeAndalucía-UniversityofPablode Olavide-University of Seville-CSIC, Seville 41092, Spain. Email: alejandro.martinmontalvo@cabimer. es FUNDING INFORMATION The authors receive financial support from the Institute of Health Carlos III and the Spanish Ministry of Science, Innovation and University, co-funded by Fondos FEDER/Fondo social Europeo (PI18/01590 and CPII19/00023 to A.M-M; CP19/00046 to V.C-G, FI19/00162 to ASG,andBFU2017-83588-PtoBRG),the Andalusian Regional Ministry of Health (C2-0024-2019toA.M-MandPI-02722017toV.C-G). Summary Thyroid function is central in the control of physiological and pathophysiological processes. Studies in animal models and human research have determined that thyroid hormones modulate cellular processes relevant for aging and for the majority of agerelated diseases. While several studies have associated mild reductions on thyroid hormone function with exceptional longevity in animals and humans, alterations in thyroid hormones are serious medical conditions associated with unhealthy aging and premature death. Moreover, both hyperthyroidism and hypothyroidism have been associated with the development of certain types of diabetes and cancers, indicating a great complexity of the molecular mechanisms controlled by thyroid hormones. In this review, we describe the latest findings in thyroid hormone research in the field of aging, diabetes, and cancer, with a special focus on hepatocellular carcinomas. While aging studies indicate that the direct modulation of thyroid hormones is not a viable strategy to promote healthy aging or longevity and the development of thyromimetics is challenging due to inefficacy and potential toxicity, we argue that interventions based on the use of modulators of thyroid hormone function might provide therapeutic benefit in certain types of diabetes and cancers. KEYWORDS cancer, diabetes, health span, hyperthyroidism, hypothyroidism, life span, thyroid hormones 2 of 25 | GAUTHIER ET Al. triiodothyronine (T3) and tetraiodothyronine (T4), also known as thyroxine, are released into the circulation. In the hypothalamus and the pituitary, THs act via the nuclear TH receptor β (THRβ) to inhibit TRH and TSH production and secretion, completing a negative feedback loop that maintains the physiological levels of TRH, TSH, and THs. In target cells, deiodinases (DIO2 and DIO3) generate T3 from T4 by removing the iodine located at the 5′ position of T4. The FIGURE 1 SchemesummarizingTHsynthesis.TRHisproducedbyaspecificgroupofneuronslocatedintheparaventricularnucleus of the hypothalamus. When TRH reaches the pituitary gland, it binds to the TRH receptor expressed in the thyrotrophs, stimulating the expression and secretion of TSH into the circulation. TSH reaches the thyroid gland and binds to the TSHR located in the cell membrane of thethyroidfollicles,settinginmotionTHproductioninaprocessthatincludestheinductionofiodineuptakebytheNIS.Iodideismobilized tothecolloidviaPendrinaction,anditisthenoxidizedbythethyroidperoxidase(TPO)usingH2O2. Iodination of tyrosine residues forms monoiodotyrosines and diiodotyrosines that are coupled to form T3 and T4. T3 and T4 bound to TG are released in the colloid of the follicle.Whenneeded,iodinatedTGiscatabolizedinthyroidfollicularepithelialcellstoproduceT3andT4,whicharethenreleasedintothe circulation. In the bloodstream, THs can be found either free or bound to serum TH-binding proteins (STHBP), such as thyroxine-binding protein, transthyretin, and albumin. Free THs are able to enter into target cells in target tissues via membrane transporters. In target cells, deiodinases generate T3 from T4 by removing the iodine located at the 5´ position of T4. Intracellular T3 acts via genomic actions binding to the THR, where modulate gene expression, or via non-genomic actions affecting signaling pathways such as integrin αvβ3 and PI3 K. THs also act via the nuclear THRβ in the hypothalamus and the pituitary to inhibit TRH and TSH production and secretion, completing a negative feedback loop that maintains physiological levels of THs. DIO: deiodinase. DUOX2: dual oxidase 2. DUOXA2: dual oxidase maturation factor 2. I−: iodide. STHBP: serum TH-binding proteins. Na+: sodium. NIS: sodium-iodide symporter. T3: triiodothyronine. T4: thyroxine. Tg: thyroglobulin. TH: thyroid hormone. THR: thyroid hormone receptors. TPO: thyroid peroxidase. TRH: thyrotropin-releasing hormone. TSH: thyrotropin. TSHR: thyrotropin receptor | 3 of 25GAUTHIER ET Al. expression of the different deiodinases is cell-type and tissue-specific, which provides a mechanism to control TH actions irrespectiveofcirculatingTHlevels(Gerebenetal.,2008;Schweizeretal., 2008). Intracellular T3 acts via binding to the TH receptor α (THRα) and THRβ, which display high affinity for DNA sequences called TH response elements (TREs). Upon ligand binding, THRs assemble into a co-activator complex with histone acetyltransferase activitythatisrecruitedtostimulatetranscription(Lonard&O'Malley, 2007;Perissietal.,2010).Moreover,THRinteractswithothernuclear hormone receptors, such as peroxisome proliferator-activated receptors, retinoid X receptors, retinoic acid receptors, and liver X receptors that allow binding to a wide repertoire of nucleotide sequences that contribute to regulate different metabolic pathways, including cholesterol, glucose, and fatty acid metabolism in different tissues(Brent,2012;Kouidhi&Clerget-Froidevaux,2018).Inaddition, THs also modulate molecular pathways via protein–protein interactionssuchasPI3K-AKT-FOXO1andmTOR-p70S6Ksignaling, which further modulate transcription (Cao et al., 2005; Davis et al., 2016;Flamantetal.,2017;Mulluretal.,2014).Inthepresenceorabsence of THs, THRs modulate the expression of more than 80 genes, mainly involved in mitochondrial biogenesis, oxidative phosphorylation, tricarboxylic acid cycle, de novo lipogenesis, and fatty acid catabolism(Flores-Moralesetal.,2002;Jackson-Hayesetal.,2003; Singh et al., 2018). Overall, THs enhance oxygen consumption and ATP hydrolysis and reduce the coupled state of the mitochondria inducingthecatabolismofalltypesofenergysources(Johannsen et al., 2012; Weinstein et al., 1991). At the organismic level, THs increase the basal metabolic rate, which is defined as rate of energy expenditure per time at rest. THs are required for the development and maturation of several tissuesandgeneralwell-being(Ngetal.,2013;Nunezetal.,2008). Hollowell et al. have defined the normal reference ranges of total T4 at 57.9–169.9nMandTSHat0.39–4.6mIU/L(Figure2)(Hollowelletal., 2002). It is estimated that in the general population the prevalence of TH alterations is ~0.5%–4% in areas with sufficient iodine exposure. There are different types of TH alterations (hyperthyroidism, subclinical hyperthyroidism, subclinical hypothyroidism, and hypothyroidism) that lead to different clinical symptoms (Figure 2) (Hollowell et al., 2002). Recent epidemiological meta-analyses have determined a clear association of TH alterations with mortality risk in the general population (Brandt et al., 2011; Kovar et al., 2015; Thvilum et al., 2012). Clinical hypothyroidism, also known as overt hypothyroidism, is associated with metabolic deregulations, such as hypercholesterolemia, and increased low-density lipoprotein (LDL) levels, that increase the risk of developing diabetes mellitus (DM) and cardiovascular complications(Cappola&Ladenson,2003;Duntas,2002;Gaoetal.,2013; Sawin et al., 1985; Taylor et al., 2013; Wang et al., 2012). Subclinical hypothyroidism has also been associated with serious complications such as improper neurocognitive health, unbalanced bone metabolism, propensity to develop type 2 DM (T2DM), cardiovascular-associated risk factors, such as high LDL and very-low-density lipoprotein (VLDL) levels, hypertriglyceridemia, hypertension, atrial fibrillation, and obesity, as well as low levels of high-density lipoprotein (HDL) and prematuremortality(Aueretal.,2001;Biondi&Cooper,2008;Biondi et al., 2002; Ceresini et al., 2013; Han et al., 2015; Pearce, 2012; Taylor et al., 2013). On the other side of the spectrum, hyperthyroid individuals also have increased risk of developing DM and cardiovascular complications that can cause premature death (Brandt et al., 2013; Franklyn et al., 2005). However, cardiovascular complications are not associated with hypercholesterolemia in hyperthyroid patients, and they normally exhibit reduced circulating cholesterol levels (Kim et al., 2020). In the case of subclinical hyperthyroidism with severely decreased TSH, clinical data indicate an increased incidence of dementiaandneurocognitivedysfunction(Aubertetal.,2017;Bensenor et al., 2010). Overt hyperthyroidism and even subclinical hyperthyroidism increase the risk of bone fractures (Blum et al., 2015; Nicholls etal.,2012;Vestergaard&Mosekilde,2003).Altogether,clinicaldata clearly indicate that in the general population TH alterations are associated with poor quality of life. 1.1 | Thyroid hormones in aging 1.1.1 | The regulation of thyroid hormones in aging and their role in longevity Early observations have established that restricted thyroid function is associated with longer life span in small and large mammals, FIGURE 2 Referencerangesandmedicalconditionsassociated with thyroid dysfunction. This figure defines reference ranges for primary hypothyroidism, secondary hypothyroidism, tertiary hypothyroidism, subclinical hypothyroidism, euthyroidism, subclinical hyperthyroidism, primary hyperthyroidism/thyroxine intoxication, and TSH-producing adenoma/resistance to THs. TSH and T4 levels were defined as Hollowell et al. Total thyroxine can beconvertedfromnMtoµg/dl,dividingby12.87.THs:thyroid hormones. TSH: thyrotropin noitartnecnoc4TlatoT TSH concentration Primary hyperthyroidism or thyroxine intoxication Primary hypothyroidism 0.1 mIU/L4.5 mIU/L 57.9 nM 169.9 nM Euthyroidism TSH-producing adenoma or resistance to THs Subclinical hyperthyroidism Subclinical hypothyroidism Secundary or tertiary hyporthyroidism (abnormal hypothalamus or pituitary function) 4 of 25 | GAUTHIER ET Al. includinghumans(Bowersetal.,2013;Buffenstein&Pinto,2009; Jansen,etal.,2015).Accordingly,higherserumTSHlevelsand/or low serum free T4 levels have been associated with longer life expectancy, indicating an important role of THs in aging (Beld et al., 2005; Gusseklooetal.,2004,2006;Rozing,etal.,2010).Althoughaging may not be considered a disease, it can be argued that the aging process is not a homogeneous physiological process. From an evolutionarypointofview,naturalselectionoptimizesmechanismsand processes that allow functionality and survival until the end of the reproductive life. However, at post-reproductive age in the majority of species, there is little natural selection to fight against mechanisms that produce unhealthy aging and death. Notwithstanding, in certain species such as humans, where familial and social interactions can be relevant for the survival of young individuals, natural selection might still have a significant role to promote longevity (Tully&Lambert,2011).Giventheseinterestingfacts,itisdifficult to define whether changes that occur in thyroid function in aged individuals are adaptive or maladaptive. Although T4 secretion has been shown to be slightly reduced inagedindividuals,thecapacitytometabolizeT4bydeiodination mediated by DIO1 and DIO2 is decreased in certain tissues of aged individuals, and healthy aged individuals exhibit normal T4 levels (Duntas,2018;Mazzoccolietal.,2010;Michalakisetal.,2013).Inthis line, old rats exhibiting comparable TSH levels to young ones have lower DIO1 activity and separated studies in rodents have demonstrated that hepatic levels of the TH transporter MCT8 are reduced in aged individuals, indicating that TH responsiveness changes with advancingage(Chakeretal.,2018;Donda&Lemarchand-Beraud, 1989). Moreover, there are evidences indicating that THs might have reduced capacity to activate certain post-receptor mechanisms of thyroid function in aged individuals (Morley, 2003). The incidence of both hyperthyroidism and hypothyroidism in the older population has continuously risen in the past decades (Boelaert,2013;Duntas,2018;Surks&Hollowell,2007).Thediagnosis of hypothyroidism in elderlies is difficult since older people exhibit milder and fewer symptoms of TH deregulation. Moreover, symptoms experienced in these patients are readily interpreted as signs of the aging process, such as fatigue and neurological disorders, whichdifficultthediagnosisofthesealterations(Martinez-Iglesias, Garcia-Siva, Regadera, et al., 2009). Prevalence of subclinical hypothyroidismaffects~6%ofthepopulationagedbetween70and 79years,risingupto10%inindividualsagedover80years(Boelaert, 2013; Simonsick et al., 2009). Noteworthy, despite the association of subclinical hypothyroidism with several serious diseases and overall mortality in the general population, a study focused on older individuals with subclinical hypothyroidism has refuted these associations (Simonsick et al., 2009). Actually, epidemiological studies in humans have even associated subclinical hypothyroidism with a reduced risk of all-cause mortality in individuals older than 65 years of age (Selmer et al., 2014). Furthermore, several reports have indicated that old individuals,ofatleast70yearsofagediagnosedwithsubclinicalhypothyroidism (TSH levels in the range of 4.5–10.0 mIU/L), might even have certain physical function advantages and lower mortality when compared to individuals with normal thyroid function (Simonsick et al., 2009, 2016). Supporting the pro-longevity benefits of reduced thyroid function in the elderly, thyroxine replacement therapy was not efficient in improving cognitive function in old patients with subclinical hypothyroidism (Park et al., 2010). The prevalence of hyperthyroidism in individuals older than 60yearsrangesfrom1%to15%(Bannister&Barnes,1989;Chiovato etal.,1997;Samuels&Feingold,2000),beingautoimmuneGraves’ disease is the most common etiology of hyperthyroidism in aged individuals. The majority of prospective studies associate higher TH concentrations with increased frailty and decreased functional capacity in old patients (Ceresini et al., 2011; Chaker et al., 2018; Simonsick et al., 2009). In this line, low levels of TSH or elevated levels of free T4 have been linked to compromised quality of life and increased mortality risk in the aged population (Gussekloo et al., 2004, 2006; Kramer et al., 2009; Parle et al., 2001; Singer, 2006; Waring, et al., 2012). The pro-aging effects of THs have been studied and active T3 binding to the THRβ isoform is known to produce DNA damage and premature senescence, making a causal connection with molecular processes of accelerated aging (Zambrano et al., 2014). Moreover, the detrimental effects of chronic hyperthyroidism in life expectancy have been observedinmiceandrats(Lopez-Noriegaetal.,2019;Ooka&Shinkai, 1986). In this sense, wild-type mice exposed to T4 leading to a twofold increase in circulating T4 levels exhibit an ~50% reduction in mean and maximallifespan(Lopez-Noriegaetal.,2019). Several studies have indicated that different TH levels within the normal range could also have physiological relevance. In this regard, high–normal free T4 levels are considered a risk factor for poor outcomes for cardiovascular disease and mortality (Hogervorst et al., 2008; Simonsick et al., 2016). Several reports have determined the effect of variations of TH levels within euthyroidism on gait speed in older people, indicating that higher TH levels are associated with slower gait speed (Bano, et al., 2016; Chaker et al., 2018; Simonsick et al., 2016). Remarkably, data in the literature indicate that subjects with low–normal free T4 levels or with high–normal TSH levels were expectedtoliveupto3.7yearslongerthanindividualswithhigh– normal free T4 levels or low–normal TSH levels (Bano et al., 2019; Chaker et al., 2018). Moreover, lower free T4 levels have been associated with better functional mobility and fitness in healthy euthyroidindividualswithagesrangingfrom68to97years,whichhasled to propose low–normal free T4 levels as a marker for healthy aging (Rozingetal.,2010;Rozingetal.,2010;Simonsicketal.,2016).In this line, lower metabolic cost of walking in adults is associated with greater gait speed and a slower decline (Schrack et al., 2012, 2016). Overall, these data are in agreement with the rate of living theory of aging, suggesting that a lower metabolic demand predisposes to longer health span and life span. 1.2 | The special case of centenarians There is strong evidence indicating that a genetic component predisposes to longevity, which is supported by studies indicating that | 5 of 25GAUTHIER ET Al. long-lived parents have long-lived offspring (Gudmundsson et al., 2000; Kerber et al., 2001; Rozing, et al., 2010). Individuals with exceptionallonglongevityintheAshkenaziJewishpopulationand their families have been studied to determine factors that could be associated with this trait. Several reports have indicated that the offspringofAshkenaziJewishcentenarianshavehigherTSHlevelsthan the offspring of non-centenarians and, even nonagenarians and their offspring, have increased TSH levels and/or decreased circulating T3/freeT4levelsthantheirpartners(Atzmonetal.,2009;Jansen, et al., 2015). The Leiden longevity study has also supported the association between low thyroid function with lower risk of death fromcardiovasculardiseaseandlongerlifespans(Rozingetal.,2010; Rozingetal.,2010;Westendorpetal.,2009).Inthisline,nonagenarians with the lowest family mortality history score had the highest TSHlevelsandslightlylowerlevelsoffreeT4andfreeT3(Rozing et al., 2010). Interestingly, TSH levels were found to be higher and free T3 levels were slightly lower when the offspring was compared totheirpartners(Rozingetal.,2010).TheLeidenlongevitystudy also analyzed nonagenarians with at least one nonagenarian sibling, their offspring, and their partners (Westendorp et al., 2009). Remarkably, authors determined that offsprings of nonagenarian siblings had lower mortality rate, and lower propensity to develop cardiovascular disease and DM than their partners. These observations have led to the conclusion that increased TSH levels are associated with exceptional longevity, which has been further supported by studies in the oldest individuals of the general population demonstrating the association of higher TSH levels with reduced old age mortality(Atzmonetal.,2009;Gusseklooetal.,2004).Anelegant workbyJansenetal.hasdeterminedTHlevelsandTSHsecretion over 24 hours in the offspring from long-lived families and their partners, since these hormones are known to have intra-day oscillations due to circadian rhythms. The objective was to evaluate alterations in energy metabolism. Results obtained led to the conclusion that familiallongevityischaracterizedbyhigherTSHsecretion,intheabsenceofalterationsonTHlevelsorenergymetabolism(Jansenetal., 2015). The lack of differences in TH levels and energy metabolism is in sharp contrast with several theories of aging postulating that reduced energy metabolism promotes longer life expectancy. Interestingly despite the fact that centenarians and their offspring tend to have lower TH function, the offspring of centenarians has a significantly lower body mass index when compared to the normal population and reduced risk of age-related diseases, further indicating a genetic component of longevity (Terry et al., 2003). Further investigationsintheAshkenaziJewishpopulationhavealsodetermined that a genetic background might be responsible for increased life span, since two specific single nucleotide polymorphisms in the TSHRgene(rs12050077andrs10149689)werelinkedtohigherTSH levels in centenarians and the offspring of centenarians of this population(Atzmonetal.,2009).BasedontheLeidenstudyandothers, one can assume that in the general population of the oldest old, high levels of TSH usually are associated with healthy aging (Gussekloo et al., 2004). The fact that TSH levels and not only TH levels are associated with extended survival suggests that modulations in the negative feedback loop controlling TH production might contribute tothisphenotype(Atzmonetal.,2009). 1.3 | The molecular mechanisms of exceptional longevity An intense area of research has been focused to identify the genetic predisposition to maximal longevity in animal models. Mutations in the DAF2 gene, homolog of the insulin-like growth factor 1 receptor (IGF-1R) in Caenorhabditis elegans and in the IGF-1R in Drosophila melanogaster, are known to extend life span (Arantes-Oliveira et al., 2003; Tatar et al., 2001). Remarkably, the longest living laboratory mice exhibit severely reduced thyroid function as observed in the Laron (growth hormone receptor knockout), Ames (Prop1-mutated), and Snell (Pit1-mutated) dwarf mice (Table 1) (Brown-Borg 2007, 2009; Brown-Borg et al., 1996). These murine models show a healthy aging phenotype that includes, besides the restriction on thyroid function, the preservation of neurocognitive and muscular function, lower incidence of cancers, enhanced insulin responsiveness, and improved glucose tolerance (Brown-Borg, 2009; BrownBorg et al., 1996; Ikeno et al., 2003; Wiesenborn et al., 2014). At a molecular level, these mice exhibit reduced signaling through the insulin and IGF-1 pathways, which leads to restricted phosphorylation of downstream targets such as the serum/glucocorticoid-regulated kinase and AKT. Restricted activity of these kinases promotes the translocation of FOXO transcription factors into the nucleus, where it modulates the transcription of genes that promote longevity(Brown-Borgetal.,1996;Russell&Kahn,2007).However, these beneficial effects on health span and/or life span might rely specifically on growth hormone production and/or sensitivity. In this context, we recently determined the direct effect of TH modulation in health span and longevity using the PAX8 knockout murine model and wild-type mice treated or not with T4 (Lopez-Noriega et al., 2019). PAX8 is the master transcriptional regulator of thyroid organogenesis required for TH production (Mansouri et al., 1998). Using these mice, we determined the effects in health status and life expectancy in mice suffering severe hypothyroidism, mild hypothyroidism, and severe hyperthyroidism compared with control healthy mice. T4-treated hyperthyroid mice exhibited reduced body weight, increased food intake, and short life expectancy, indicating that elevated TH levels result in life-threatening toxicity. Not surprisingly, the complete lack of TH production resulted in perinatal mortality(Lopez-Noriegaetal.,2019).ThedirectmodulationofTH levelsusingPAX8heterozygousknockoutmice,whichsufferamild hypothyroidism due to a direct defect in the thyroid gland, while exhibiting normal circulating levels of α-GSU of pituitary hormones in adulthood, did not result in improved health span or longer life span. As opposed to other experimental models of hypothyroidism (Hine etal.,2017;Umezuetal.,2020),wefoundthatthePAX8heterozygous mice faithfully recapitulate the phenotype of humans with hypothyroidism, including insulin resistance, increased white adipose tissue (WAT) mass, and increased triglyceride content in skeletal 6 of 25 | GAUTHIER ET Al. muscle and liver (Lopez-Noriega et al., 2019). Similar to humans, these mice also exhibit reduced basal metabolic rate and obesity whilemaintainingnormalenergyintake.Moreover,PAX8heterozygous mice exhibit poor performance in functional physical tests and accumulated oxidative damage, indicating that even mild alterations on TH levels (mild hypothyroidism) have profound effects in health span. These results indicate that low TH levels in exceptional longliving dwarf mice are not responsible per se of longevity benefits. Our data support the notion that humans with exceptional longevity must have a specific genetic and/or epigenetic signature required to achieve longevity benefits (Bowers et al., 2013; Gesing et al., 2012; Jansen,etal.,2015).Inaddition,ourdataalsoindicatethatadelicate control of TH levels and function is required to sustain health and survival and that interventions based on the modulation of THs should not be targeted to improve the quality of life or life expectancy in healthy individuals. 1.4 | The effect of nutritional and pro-longevity interventions in thyroid function Several animals, including humans under calorie restriction, a variety of nutritional interventions that extend health span and lifespan, have low T3 and/or high TSH levels in the blood (De Andrade et al., 2015; Fontana et al., 2006; Muller et al., 2015; Ravussin et al., 2015). Remarkably, a recent report evaluating the effects of 4-week alternate day fasting has clearly demonstrated a reduction in T3 levels in individuals adhered to the intervention, which is accompanied by improvements in markers of cardiovascular health (Stekovic et al., 2020). In this line, a caloric restriction mimetic, resveratrol, rises TSH levels and has profound effects in the thyroid gland, decreasing sodium-iodide symporter (NIS) and thyroglobulin (TG) expression(Giulianietal.,2017).Calorierestrictionproduceseffectsatall compartments of the HPT axis, as well as in TH target tissues. In particular, reduced hypothalamic TRH expression, reduced pituitary TSHβ expression, reduced expression of TG and secretion of T3 and T4 in the thyroid gland, and reduced hepatic DIO1 expression have been described upon different forms of caloric restriction (Boelen et al., 2008; De Andrade et al., 2015; Palkowska-Gozdzik et al., 2017). Different nutritional interventions are also known to alter TH levels. In this regard, adult dogs consuming a low-carbohydrate high-protein high-fat diet exhibited greater circulating T4 levels than dogs fed with a high-carbohydrate low-protein low-fat diet (Chiofalo et al., 2019). Interestingly, Carew et al. evaluated the effect of individual essential amino acid restriction on plasma TH concentrations inchickens(Carewetal.,1997).Resultsindicatedthatchangesincirculating levels of T3 under protein deficiency may be a consequence of selected amino acid deficits, since only isoleucine deficiency resulted in an elevation in plasma T3, while restrictions on other essential amino acids did not alter T3 levels when compared to control fed chickens. However, the molecular mechanisms producing these changes remain unknown. 1.5 | Thyroid hormones in diabetes mellitus 1.5.1 | The implications of thyroid hormones in glucose and lipid metabolism As previously mentioned, THs enhance oxygen consumption, inducingthecatabolismofalltypesofenergysources(Johannsenetal., 2012; Weinstein et al., 1991). THs are efficient modulators of lipid and glucose metabolism. In particular, THs reduce circulating triglycerides and cholesterol-containing lipoproteins. THs stimulate the expression of the Sterol response element-binding protein 2 (Srebp2) (Mullur et al., 2014). Increased levels of Srebp-2 contribute to enhance LDL receptor expression, which potentiates hepatic cholesterol uptake. Moreover, THs are known to increase simultaneously lipolysis and liponeogenesis. Actually, THs are known to increase the expression of carnitine palmitoyltransferase Iα (mitochondrial fatty acid uptake) and the acetyl-coenzyme A carboxylase (lipogenic) (Mullur et al., 2014). A comprehensive analysis of these processes has indicated that liponeogenesis is enhanced to maintain lipid levels under conditions of high lipolysis (Oppenheimer et al., 1991). Under these circumstances, lipolysis is enhanced to provide substrates for thermogenesis. Carbohydrate metabolism is also influenced by TH. Gluconeogenesis and glycogenolysis are known to be enhanced by THs in a process that supports tissues with fuel to maintain their energy requirements. In this sense, hepatic insulin resistance in hyperthyroid individuals has been shown to increase gluconeogenesis and subsequent hepatic glucose output (Figure 3) (Klieverik et al., 2008;Potenzaetal.,2009).Increasedratesofgluconeogenesisare supported by increased Cory cycle activity, which implicates muscle tissue in the provision of substrates for hepatic gluconeogenesis (lactate and certain amino acids such as alanine and glutamine). This process represents a dynamic buffer of glucose that allows its use by other tissues under glucose requirements when needed. Within the liver, THs are known to enhance the expression of the phosphoenolpyruvate carboxykinase, the rate-limiting step in gluconeogenesis, supporting a direct role of THs in the regulation of these processes (Park et al., 1999). Studies in mice exposed to T4 mimicking hyperthyroidism have also indicated that insulin signaling is active in insulin-target tissues even under fasting conditions, due to a deregulated function of the endocrine pancreas (e.g., increased insulinsecretionandsubsequentlevelsincirculation)(Lopez-Noriega etal.,2017).Overall,compellingdataintheliteratureindicatethat THs produce effects in several, if not all, tissues involved in glucose and lipid homeostasis (Figure 3). 1.5.2 | Alterations of thyroid hormones in diabetes mellitus The relationship between alterations on thyroid function and the development of different types of DM has been the focus of intense research. The prevalence of hyperthyroidism in subjects suffering DM | 7 of 25GAUTHIER ET Al. TABLE 1 Geneticalterationscausingthyroiddysfunctionassociatedwithaging,DM,orcancerinmiceandhumans.ND:notdetermined Gene Function Alteration Phenotype ReferencesAging DM Cancer DIO2 TH activation/ inactivation Homozygous knockout mouse ND Several hallmarks of T2DM ND Marsili et al. (2011) SNPs in humans ND Several hallmarks of T2DM ND Canani et al. (2005); Dora et al. (2010); Mentuccia et al. (2002) DUOX2 TH production SNPs in humans ND ND Predisposes to thyroid cancer Bann et al. (2019) TG TH transport SNPs in humans ND ND Found in thyroid cancer Hishinuma et al., 2005) THRαTH signaling Homozygous knockout mouse ND Protected from hallmarks of T2DM ND Jornayvazetal.(2012) Truncations and SNPs in cancer tissue in humans ND ND Found in several types of cancer Kim and Cheng (1830); Lin et al. (1999); Kamiya et al. (2002); PuzianowskaKuznickaetal. (2002); Chan and Privalsky (2006); Rosen and Privalsky (2011) McCabe et al. (1999); Cheng (2003) THRβTH signaling Truncations and SNPs in cancer tissue in humans ND ND Found in several types of cancer Kim and Cheng (1830); Lin et al. (1999); Kamiya et al. (2002); PuzianowskaKuznickaetal. (2002); Chan and Privalsky (2006); Rosen and Privalsky (2011); Cheng (2003) TSHR TSH signaling Homozygous knockout mouse Premature death Glucose intolerance ND Abe et al. (2003); Yang et al. (2019) Truncations and SNPs in cancer tissue in humans ND ND Mutations found in HCC and thyroid cancer Shih et al. (2018); Russo et al. (1995); Camacho et al. (2000) PAX8 Thyroid development and function. Homozygous knockout mouse Premature death No No Lopez-Noriegaetal. (2019); Mansouri et al. (1998) Heterozygous knockout mouse Unhealthy aging; normal life span Several hallmarks of T2DM Liver cancer Lopez-Noriegaetal. (2019) Human SNPs ND GDM Propensity to HCC Martin-Montalvo et al. (2019); Ma et al. (2017) (Continues) 8 of 25 | GAUTHIER ET Al. is greater than in non-diabetic subjects (Biondi et al., 2019), and a nationwide Danish study has determined that patients suffering hyperthyroidism have greater risk to develop DM (Brandt et al., 2013). Among adult patients with T2DM, ~4.4% have overt hyperthyroidism and 2%–4% have subclinical hyperthyroidism (Biondi et al., 2019). Interestingly, improved diabetic control in T2DM patients normalizes TSH levels in patients with subclinical hyperthyroidism, suggesting that treatments improving T2DM might contribute tonormalizethyroidfunction(Celanietal.,1994).However,arecent report has indicated that non-diabetic patients diagnosed with hyperthyroidism have increased risk to develop T2DM later in life, suggesting that thyroid dysfunction might precede diabetogenic processes (Chen et al., 2019). In this line, while hyperthyroid patients exhibit increased basal hepatic glucose production and increased fasting insulin levels when compared to healthy individuals, hyperthyroid patients treated with methimazole rendered euthyroid, exhibited significantly reduced levels on the same parameters, reaching the levels of the healthy control group (Cavallo-Perin et al., 1988). An independent report has also indicated that patients with overt or subclinical hyperthyroidism exposed to a glucose tolerance test have higher circulating levels of glucose and insulin (Maratou et al., 2010). Glucose intolerance in these patients is due to potentiated hepatic gluconeogenesis (Maratou et al., 2010). These effects might be related to the control that exerts THs in the expression of genes involved in glucose and lipid metabolism and suggests that several physiological aberrations are common to hyperthyroidism and T2DM, which contribute to the loss of metabolic homeostasis. Longitudinal studies have also investigated the association of alterations in thyroid function and the prevalence of DM and metabolic syndrome in older adults (Heima et al., 2013; Waring, et al., 2012). At baseline, individuals in the metabolic syndrome group exhibited significantly higher TSH values than individuals not included in the metabolic syndrome group. The authors indicated that increased circulating levels of TSH were associated with greater prevalence of metabolic syndrome, even in participants within the normal range (Waring et al., 2012). Another longitudinal study performed in Amsterdam also associated higher prevalence of metabolic syndrome and obesity with individuals exhibiting higher circulating levels of TSH (Heima et al., 2013). Separated research as also indicated that hypothyroidism is associated with insulin resistance and dyslipidemia(Dimitriadisetal.,2006;Gierach&Junik,2015;Wang, 2013). Further evidence also indicates an increased risk of DM in patients with hypothyroidism and a systematic review reported the increased prevalence of even subclinical hypothyroidism in patients with T2DM (Gronich et al., 2015; Han et al., 2015). As opposed to compelling research indicating the association of DM and thyroid dysfunction, which is supported by the well-described role of THs on glucose metabolism and insulin secretion, other studies have failed to link hypothyroidism to the development of T2DM (Ishay et al., 2009; Radaideh et al., 2004). A growing evidence is associating alterations in thyroid function with other types of DM such as type 1 DM (T1DM) and gestational DM (GDM). Several studies have shown that patients with T1DM, an autoimmune disease, are prone to exhibit autoimmune thyroiddiseasessuchasHashimoto'sthyroiditisandGraves’disease. Current data indicate that up to 30% of adults with T1DM have thyroid diseases of autoimmune origin (Araujo et al., 2008; Shun et al., 2014). Genetic studies have revealed susceptibility genes for this syndrome, which include the human leukocyte antigen, cytotoxic T-lymphocyte-associated antigen 4, protein tyrosine phosphatase non-receptor type 22, forkhead box P3, and the interleukin-2 receptoralpha/CD25generegion(Dittmar&Kahaly,2010).Thesegenes are involved in immunological synapse and T-cell activation, suggesting that similar pathogenic processes occur in T1DM and thyroid diseasesofautoimmuneorigin(Dittmar&Kahaly,2010). Gestational DM is a common complication that affects ~10% of all pregnancies associated with adverse pregnancy outcomes, such as preeclampsia, macrosomia, and caesarean delivery (International Association of Diabetes, 2010; Petra et al., 2019). Upon delivery, GDM disappears but in many cases different types of DM (GDM in a subsequent pregnancy or T2DM) can spur later in life (Martin etal.,1999;Seely&Solomon,2003).Amongthechangesthatoccur during pregnancy, it is known that the placenta increases the secretion of pro-inflammatory cytokines that induce insulin resistance to favor nutrient availability to the fetus (Kim et al., 2010). Under these circumstances (e.g., transient insulin resistance during pregnancy), GDM is the result of compromised capacity of pancreatic β-cells to increase insulin secretion to compensate insulin resistance in insulin-target tissues (Kuhl, 1991). Several reports have determined that maternal hypothyroidism predisposes the offspring to exhibit limited Gene Function Alteration Phenotype ReferencesAging DM Cancer PIT-1 TRH/TSH production Homozygouslossof-function point mutation in mouse Delayed aging Increased insulin sensitivity Reduced occurrence of spontaneous cancer Brown-Borg(2007); Flurkey et al. (2001); Alderman et al. (2009) PROP-1 TRH/TSH production Homozygouslossof-function point mutation in mouse Delayed aging Increased insulin sensitivity Delayed spontaneous occurrence of cancer Brown-Borg(2007) Brown-Borg et al. (1996); Ikeno et al. (2003) TABLE1 (Continued) | 9 of 25GAUTHIER ET Al. insulin secretion and to develop glucose intolerance, increasing the risk of T2DM in the offspring (Karbalaei et al., 2013). Moreover, separated reports have also determined that hypothyroidism is associated with GDM (Martin-Montalvo et al., 2019; Sell et al., 2008). In this regard, we found several mutations in PAX8 leading to hypothyroidism associated with the development of GDM, indicating that human GDM could have a genetic component (Martin-Montalvo et al., 2019). Remarkably, this work has revealed that PAX8 expression in pancreatic islets modulates cellular pathways involved in cellular survival (Martin-Montalvo et al., 2019). 1.5.3 | The physiological and pathophysiological role of thyroid hormones in the endocrine pancreas One of the main organs involved in the control of circulating glucose levels is the endocrine pancreas. Extensive research has demonstrated the role of THs in the differentiation, maturation, and functionalityofmetabolictissues(Figure3)(Mastracci&Evans-Molina, 2014). In vivo research has determined that during postnatal development circulating levels of T3 increase and induce the expression of the MAF bZIP transcription factor A (MAFA) and THRs in pancreatic FIGURE 3 SchemesummarizingtheprocessesregulatedbyTHsinthemainmetabolictissues.THsexertprofoundeffectsinmetabolic tissues. THs enhance GK and MAFA expression in the pancreas favoring a rapid maturation and turnover of β cells. THs also potentiate insulin expression and secretion in the endocrine pancreas. Insulin-target tissues respond increasing the activity of insulin signaling, which produces increased rates of lipolysis and gluconeogenesis in the liver and proteolysis and mitochondrial biogenesis in the skeletal muscle. AdiposetissuesrespondtoTHsincreasinglipolysisandlipidmobilization.Browning/beigingofadipocytesoccursintheWATandincreasing thermogenesis via increased UCP expression and subsequent lipolysis occurs in the BAT. AKT, protein kinase B. 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