Hiperglucemia en ayunas y polimorfismo en el promotor de la glucoquinasa (rs1799884) / Fasting hyperglycaemia and polymorphism in glucokinase promoter (rs1799884)

La glucoquinasa es uno de los principales reguladores de la glucemia plasmática en ayunas. Numerosas mutaciones en el gen de la glucoquinasa (GCK) se han identificado como base molecular de la diabetes monogénica. Recientemente se han descrito polimorfismos en su promotor que se asocian a incrementos en la glucemia plasmática en ayunas. Se presenta a un niño de 7 años y 7 meses con sobrepeso y antecedentes de diabetes en dos generaciones previas. En la sobrecarga oral de glucosa presentó alteración de la glucemia en ayunas y a las 2h, con respuesta de insulina elevada. Las alteraciones analíticas mejoraron tras pérdida ponderal manteniendo una discreta hiperglucemia en ayunas. El estudio de las diabetes monogénicas más frecuentes, MODY subtipos 1, 2 y 3, fue negativo, encontrándose la variante alélica (G/A) en el polimorfismo rs1799884, localizado en el promotor de GCK (AU)

Glucokinase is one of the most important regulators of fasting glucose levels. There are several mutations in the glucokinase gene (GCK) which are linked with monogenic diabetes. Recently, a polymorphism in its promoter has been described, which is associated with impaired fasting glucose levels. We present a 7 years and 7 months old boy with overweight and a familial background of diabetes in two previous generations. In the oral glucose tolerance test, he had impaired fasting glucose levels and after two hours, with a high insulin response. Laboratory abnormalities improved after weight loss, but he maintains a slight fasting hyperglycaemia. The molecular study of the most common monogenic diabetes forms, MODY subtypes 1, 2, and 3, was negative. The allelic variant G/A was however detected at the GCK promoter polymorphism rs1799884 (AU)

[Fasting hyperglycaemia and polymorphism in glucokinase promoter (rs1799884)]. / Hiperglucemia en ayunas y polimorfismo en el promotor de la glucoquinasa (rs1799884).

Glucokinase is one of the most important regulators of fasting glucose levels. There are several mutations in the glucokinase gene (GCK) which are linked with monogenic diabetes. Recently, a polymorphism in its promoter has been described, which is associated with impaired fasting glucose levels. We present a 7 years and 7 months old boy with overweight and a familial background of diabetes in two previous generations. In the oral glucose tolerance test, he had impaired fasting glucose levels and after two hours, with a high insulin response. Laboratory abnormalities improved after weight loss, but he maintains a slight fasting hyperglycaemia. The molecular study of the most common monogenic diabetes forms, MODY subtypes 1, 2, and 3, was negative. The allelic variant G/A was however detected at the GCK promoter polymorphism rs1799884.

Clinical and molecular evaluation of SHOX/PAR1 duplications in Leri-Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS).

CONTEXT: Léri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterized by disproportionate short stature and the Madelung deformity of the forearm. SHOX mutations and pseudoautosomal region 1 deletions encompassing SHOX or its enhancers have been identified in approximately 60% of LWD and approximately 15% of idiopathic short stature (ISS) individuals. Recently SHOX duplications have been described in LWD/ISS but also in individuals with other clinical manifestations, thus questioning their pathogenicity. OBJECTIVE: The objective of the study was to investigate the pathogenicity of SHOX duplications in LWD and ISS. DESIGN AND METHODS: Multiplex ligation-dependent probe amplification is routinely used in our unit to analyze for SHOX/pseudoautosomal region 1 copy number changes in LWD/ISS referrals. Quantitative PCR, microsatellite marker, and fluorescence in situ hybridization analysis were undertaken to confirm all identified duplications. RESULTS: During the routine analysis of 122 LWD and 613 ISS referrals, a total of four complete and 10 partial SHOX duplications or multiple copy number (n > 3) as well as one duplication of the SHOX 5' flanking region were identified in nine LWD and six ISS cases. Partial SHOX duplications appeared to have a more deleterious effect on skeletal dysplasia and height gain than complete SHOX duplications. Importantly, no increase in SHOX copy number was identified in 340 individuals with normal stature or 104 overgrowth referrals. CONCLUSION: MLPA analysis of SHOX/PAR1 led to the identification of partial and complete SHOX duplications or multiple copies associated with LWD or ISS, suggesting that they may represent an additional class of mutations implicated in the molecular etiology of these clinical entities.

CDKN1C mutations in HELLP/preeclamptic mothers of Beckwith-Wiedemann Syndrome (BWS) patients.

Preeclampsia is the development of new-onset hypertension with proteinuria after 20 weeks of gestation. HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet count) is a severe form of preeclampsia with high rates of neonatal and maternal morbidity. In recent years, loss of function of cdkn1c (a tight-binding inhibitor of G1 cyclin/cyclin-dependent kinase complexes and a negative regulator of cell proliferation) has been observed in several mouse models of preeclampsia. In this paper, we report on three women with HELLP/preeclampsia who had children with Beckwith Wiedemann syndrome, a complex genetic disorder characterised, among other findings, by overgrowth, omphalocele and macroglossia. All three children displayed mutations in CDKN1C predicted to generate truncated proteins. Two of the mutations were maternally inherited while the third was de novo. This finding suggests a fetal contribution to the maternal disease. To the best of our knowledge this is the first report of CDKN1C mutations in children born to women with preeclampsia/HELLP syndrome, thus suggesting the involvement of an imprinted gene in the pathophysiology of preeclampsia.

Permanent neonatal diabetes caused by a homozygous nonsense mutation in the glucokinase gene.

Glucokinase deficiency is an unfrequent cause of permanent neonatal diabetes (PND), as only seven patients have been reported, either homozygous for a missense or frameshift mutation or compound heterozygous for both of them. We report here the first known case caused by a homozygous nonsense mutation (Y61X) in the glucokinase gene (GCK) that introduces a premature stop codon, generating a truncated protein that is predicted to be completely inactive as it lacks both the glucose- and the adenosine triphosphate-binding sites. The proband, born to consanguineous parents, was a full-term, intra-uterine growth-retarded male newborn who presented with a glycaemia of 129 mg/dL (7.16 mmol/L) on his second day of life, increasing thereafter up to 288 mg/dL (15.98 mmol/L) and 530 mg/dL (29.41 mmol/L) over the next 24 h, in the face of low serum insulin (<3 muIU/mL; <20.83 pmol/L). He was put on insulin on the third day of life. Insulin has never been discontinued since then. The patient was tested negative for anti-insulin and islet cell antibodies at age 5 months. His father had non-progressive, impaired fasting glucose for several years. The mother was found to be mildly hyperglycaemic only when her glucose was checked after the child was diagnosed. In conclusion, biallelic GCK loss should be considered as a potential cause of PND in children born to consanguineous parents, even if they are not known to be diabetic at the time of PND presentation.

Diabetes mellitus neonatal: complejidad clínica y heterogenidad genética / Neonatal diabetes mellitus: clinical complexity and genetic heterogeneity

La mayoría de los casos de diabetes mellitus (DM) que se diagnostican en niños prepuberales tiene una bese autoinmune. Sin embargo, en los últimos años se ha hecho cada vez más evidente que la DM neonatal, definida como la existencia de hiperglucemia en los primeros seis meses de vida en recién nacidos a término, tiene un origen radicalmente distinto. En este grupo de pacientes, las manifestaciones autoinmunes son excepcionales pero, en cambio, se han descrito numerosas formas de DM debidas a alteraciones genéticas involucradas en el desarrollo embrionario o la funcionalidad del páncreas, que pueden ser transitorias o permanentes. Su correcta identificación amplía las posibilidades etiológicas y explica algunos síndromes complejos y poco frecuentes. Por el momento, se han identificado 13 subtipos distintos de DM neonatal en el ser humano, secundarios a mutaciones en otros tantos genes: ZAC, IPF-1, PTF1A, HNF-1β, GLIS3, GCK, KCNJ11, ABCC8, SLC2A2, SLC19A2, EIF2AK3, FOXP3 e INSR. El estudio molecular de los pacientes con DM neonatal tiene una repercusión clínica inmediata, ya que puede ayudar a distinguir las formas de DM neonatal transitorias de las permanentes y en ocasiones, permite realizar cambios en la forma de tratamiento de algunos pacientes que conllevan una notable mejoría de su control metabólico y su calidad de vida (AU)

Most cases of diabetes mellitus (DM) diagnosed in prepubertal children have an autoinmune cause. However, evidence supports the hypothesis that neonatal DM, defined as the presence of hypothesis that neonatal DM, defined as the presence of hyperglycemia within the first six months of life in full-term newborns, has a completely different origin. Indeed, in this group of patients an autoimmune cause is exceptional. In contrast, multiple forms od DM are due to genetic abnormalities affecting either embryonic development or pancreatic function. In addition, neonatal DM can be transient or permanent. Molecular diagnosis is necessary and could help to explain some complex and rare syndromes. To date, 13 different subtypes of neonatal DM, secondary to the presence of mutations in 123 different genes, have been reported: ZAC, IPF-1, PTF1A, HNF-1β, GLIS3, GCK, KCNJ11, ABCC8, SLC2A2, SLC19A2, EIF2AK3, FOXP3 and INSR. The molecular study of patients with neonatal DM could help to distinguish between transient and permanent forms and sometimes this information can be used to modify therapy, improving the patient´s metabolic control and quality of life (AU)

Protective effects of insulin-like growth factor-I on the somatostatinergic system in the temporal cortex of beta-amyloid-treated rats.

Insulin-like growth factor-I (IGF-I) has protective effects against beta-amyloid (Abeta)-induced neuronal cell death. Because alterations of the somatostatinergic system have been described in Alzheimer's disease, we investigated the effects of the Abeta peptide and the possible protective role of IGF-I on the somatostatinergic system of the rat temporal cortex and on cell death and phosphorylated (p)-Akt levels in this area. Abeta25-35 was administered intracerebroventricularly to male rats via an osmotic minipump over 14 days (300 pmol/day). Another group received a subcutaneous IGF-I infusion (50 microg/kg/day), concomitant with Abeta25-35 administration, whereas a third group received IGF-I alone. Abeta25-35 significantly decreased the somatostatin (SRIF)-like immunoreactive content and the SRIF receptor density, as a result of a decrease in the levels of the SRIF receptor subtype 2. The inhibitory effect of SRIF on adenylyl cyclase activity was significantly lower after Abeta25-35 infusion, whereas the levels of the inhibitory G protein subunit Gialpha1, Gialpha2 or Gialpha3 were unaltered. Cell death was increased and p-Akt levels decreased in Abeta25-35-treated animals. IGF-I administration increased immunoreactive IGF-I levels in the temporal cortex and restored all parameters affected by Abeta25-35 to baseline values. These findings suggest that IGF-I prevents the deleterious effect of Abeta25-35 on the somatostatinergic system.

Bases moleculares del hipocrecimiento armónico / Molecular bases of harmonic hypogrowth

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Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes.

May-Hegglin anomaly (MHA) and Fechtner (FTNS) and Sebastian (SBS) syndromes are autosomal dominant platelet disorders that share macrothrombocytopenia and characteristic leukocyte inclusions. FTNS has the additional clinical features of nephritis, deafness, and cataracts. Previously, mutations in the nonmuscle myosin heavy chain 9 gene (MYH9), which encodes nonmuscle myosin heavy chain IIA (MYHIIA), were identified in all three disorders. The spectrum of mutations and the genotype-phenotype and structure-function relationships in a large cohort of affected individuals (n=27) has now been examined. Moreover, it is demonstrated that MYH9 mutations also result in two other FTNS-like macrothrombocytopenia syndromes: Epstein syndrome (EPS) and Alport syndrome with macrothrombocytopenia (APSM). In all five disorders, MYH9 mutations were identified in 20/27 (74%) affected individuals. Four mutations, R702C, D1424N, E1841K, and R1933X, were most frequent. R702C and R702H mutations were only associated with FTNS, EPS, or APSM, thus defining a region of MYHIIA critical in the combined pathogenesis of macrothrombocytopenia, nephritis, and deafness. The E1841K, D1424N, and R1933X coiled-coil domain mutations were common to both MHA and FTNS. Haplotype analysis using three novel microsatellite markers revealed that three E1841K carriers--one with MHA and two with FTNS--shared a common haplotype around the MYH9 gene, suggesting a common ancestor. The two new globular-head mutations, K371N and R702H, as well as the recently identified MYH9 mutation, R705H, which results in DFNA17, were modeled on the basis of X-ray crystallographic data. Altogether, our data suggest that MHA, SBS, FTNS, EPS, and APSM comprise a phenotypic spectrum of disorders, all caused by MYH9 mutations. On the basis of our genetic analyses, the name "MYHIIA syndrome" is proposed to encompass all of these disorders.

Distinct tissue-specific roles for thyroid hormone receptors beta and alpha1 in regulation of type 1 deiodinase expression.

Type 1 deiodinase (D1) metabolizes different forms of thyroid hormones to control levels of T3, the active ligand for thyroid hormone receptors (TR). The D1 gene is itself T3-inducible and here, the regulation of D1 expression by TRalpha1 and TRbeta, which act as T3-dependent transcription factors, was investigated in receptor-deficient mice. Liver and kidney D1 mRNA and activity levels were reduced in TRbeta(-/-) but not TRalpha1(-/-) mice. Liver D1 remained weakly T3 inducible in TRbeta(-/-) mice whereas induction was abolished in double mutant TRalpha1(-/-)TRbeta(-/-) mice. This indicates that TRbeta is primarily responsible for regulating D1 expression whereas TRalpha1 has only a minor role. In kidney, despite the expression of both TRalpha1 and TRbeta, regulation relied solely on TRbeta, thus revealing a marked tissue restriction in TR isotype utilization. Although TRbeta and TRalpha1 mediate similar functions in vitro, these results demonstrate differential roles in regulating D1 expression in vivo and suggest that tissue-specific factors and structural distinctions between TR isotypes contribute to functional specificity. Remarkably, there was an obligatory requirement for a TR, whether TRbeta or TRalpha1, for any detectable D1 expression in liver. This suggests a novel paradigm of gene regulation in which the TR sets both basal expression and the spectrum of induced states. Physiologically, these findings suggest a critical role for TRbeta in regulating the thyroid hormone status through D1-mediated metabolism.

Type 2 iodothyronine deiodinase expression in the cochlea before the onset of hearing.

Thyroid hormone signaling during a postnatal period in the mouse is essential for cochlear development and the subsequent onset of hearing. To study the control of this temporal dependency, we investigated the role of iodothyronine deiodinases, which in target tissues convert the prohormone thyroxine into triiodothyronine (T3), the active ligand for the thyroid hormone receptor (TR). Type 2 5'-deiodinase (D2) activity rose dramatically in the mouse cochlea to peak around postnatal day 7 (P7), after which activity declined by P10. This activity peak a few days before the onset of hearing suggests a role for D2 in amplifying local T3 levels at a critical stage of cochlear development. A mouse cochlear D2 cDNA was isolated and demonstrated near identity to rat D2. In situ hybridization localized D2 mRNA in periosteal connective tissue in the modiolus, the cochlear outer capsule and the septal divisions between the turns of the cochlea. Surprisingly, D2 expression in these regions that give rise to the bony labyrinth was complementary to TR expression in the sensory epithelium. Thus, the connective tissue may control deiodination of thyroxine and release of T3 to confer a paracrine-like control of TR activation. These results suggest that temporal and spatial control of ligand availability conferred by D2 provides an unexpectedly important level of regulation of the TR pathways required for cochlear maturation.

Thyroid hormone is essential for pituitary somatotropes and lactotropes.

Mice homozygous for a disruption in the alpha-subunit essential for TSH, LH, and FSH activity (alphaGsu-/-) exhibit hypothyroidism and hypogonadism similar to that observed in TSH receptor-deficient hypothyroid mice (hyt) and GnRH-deficient hypogonadal mutants (hpg). Although the five major hormone-producing cells of the anterior pituitary are present in alphaGsu-/- mice, the relative proportions of each cell type are altered dramatically. Thyrotropes exhibit hypertrophy and hyperplasia, and somatotropes and lactotropes are underrepresented. The size and number of gonadotropes in alphaGsu mutants are not remarkable in contrast to the hypertrophy characteristic of gonadectomized animals. The reduction in lactotropes is more severe in alphaGsu mutants (13-fold relative to wild-type) than in hyt or hpg mutants (4.5- and 1.5-fold, respectively). In addition, T4 replacement therapy of alphaGsu mutants restores lactotropes to near-normal levels, illustrating the importance of T4, but not alpha-subunit, for lactotrope proliferation and function. T4 replacement is permissive for gonadotrope hypertrophy in alphaGsu mutants, consistent with the role for T4 in the function of gonadotropes. This study reveals the importance of thyroid hormone in developing the appropriate proportions of anterior pituitary cell types.

Novel insight from transgenic mice into thyroid hormone resistance and the regulation of thyrotropin.

Patients with resistance to thyroid hormone (RTH) exhibit elevated thyroid hormone levels and inappropriate thyrotropin (thyroid-stimulating hormone, or TSH) production. The molecular basis of this disorder resides in the dominant inhibition of endogenous thyroid hormone receptors (TRs) by a mutant receptor. To determine the relative contributions of pituitary versus hypothalamic resistance to the dysregulated production of thyroid hormone in these patients, we developed a transgenic mouse model with pituitary-specific expression of a mutant TR (Delta337T). The equivalent mutation in humans is associated with severe generalized RTH. Transgenic mice developed profound pituitary resistance to thyroid hormone, as demonstrated by markedly elevated baseline and non-triodothyronine (T3)-suppressible serum TSH and pituitary TSH-beta mRNA. Serum thyroxine (T4) levels were only marginally elevated in transgenic mice and thyrotropin-releasing hormone (TRH) gene expression in the paraventricular hypothalamus was downregulated. After TRH administration, T4 concentrations increased markedly in transgenic, but not in wild-type mice. Transgenic mice rendered hypothyroid exhibited a TSH response that was only 30% of the response observed in wild-type animals. These findings indicate that pituitary expression of this mutant TR impairs both T3-mediated suppression and T3-independent activation of TSH production in vivo. The discordance between basal TSH and T4 levels and the reversal with TRH administration demonstrates that resistance at the level of both the thyrotroph and the hypothalamic TRH neurons are required to elevate thyroid hormone levels in patients with RTH.

Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1.

Thyroid hormone, acting through several nuclear hormone receptors, plays important roles in thermogenesis, lipogenesis and maturation of the neonatal brain. The receptor specificity for mediating these effects is largely unknown, and to determine this we developed mice lacking the thyroid hormone receptor TR alpha 1. The mice have an average heart rate 20% lower than that of control animals, both under normal conditions and after thyroid hormone stimulation. Electrocardiograms show that the mice also have prolonged QRS- and QTend-durations. The mice have a body temperature 0.5 degrees C lower than normal and exhibit a mild hypothyroidism, whereas their overall behavior and reproduction are normal. The results identify specific and important roles for TR alpha 1 in regulation of tightly controlled physiological functions, such as cardiac pacemaking, ventricular repolarisation and control of body temperature.

Effects of selenium and iodine deficiency on thyroid hormone concentrations in the central nervous system of the rat.

OBJECTIVE: The effects of single and combined nutritional selenium and iodine deficiency on intracellular thyroid hormone concentrations and type II 5'-iodothyronine deiodinase (5'D-II) activity were examined in different regions of the adult rat brain. DESIGN: Four groups (n = 6) of weanling female Wistar rats proceeding from a breeding line fed a selenium-deficient or a selenium-replete diet for 3 generations, were fed selenium-deficient, iodine-deficient, combined selenium- and iodine-deficient or selenium- and iodine-replete diets for 2 months before they were killed. METHODS: Tissue thyroxine (T4) and tri-iodothyronine (T3) concentrations were determined by highly sensitive RIAs after extraction of the iodothyronines from the tissue samples. The measurement of 5'D-II was based on the release of radioiodide from the 125I-labelled substrate. RESULTS: Selenium deficiency significantly decreased tissue T3 concentrations in the hippocampus, hypothalamus and striatum to 70-80% of controls, whereas no significant changes were found in the cerebellum, cerebral cortex and brain stem. Tissue T4 concentrations were only marginally affected with the exception of a 35% increase in the cerebral cortex. Iodine deficiency dramatically diminished serum T4 levels as well as intracellular T4 concentrations in all regions examined up to 10-30% of control. In spite of a threefold enhancement of 5'D-II, the iodine-deficient animals still had a significant reduction of tissue T3 concentrations (50-65% of controls) in all regions excepting the cerebellum. The combination of selenium and iodine deficiency did not significantly alter this pattern of changes. CONCLUSIONS: These findings suggest that prolonged selenium deficiency as well as iodine deficiency may compromise thyroid hormone homeostasis in the adult brain leading to tissue hypothyroidism and therefore to impaired brain function.

Evidence for circadian variations of thyroid hormone concentrations and type II 5'-iodothyronine deiodinase activity in the rat central nervous system.

The 24-h patterns of tissue thyroid hormone concentrations and type II 5'- and type III 5-iodothyronine deiodinase (5'D-II and 5D-III, respectively) activities were determined at 4-h intervals in different brain regions of male euthyroid rats entrained to a regular 12-h light/12-h dark cycle (lights on at 6:00 a.m.). Activity of 5'D-II, which catalyzes the intracellular conversion of thyroxine (T4) to 3,3',5-triiodo-L-thyronine (T3) in the CNS, and the tissue concentrations of both T4 and T3 exhibited significant daily variations in all brain regions examined. Periodic regression analysis revealed significant circadian rhythms with amplitudes ranging from 9 to 23% (for T3) and from 15 to 40% (for T4 and 5'D-II) of the daily mean value. 5'D-II activity showed a marked nocturnal increase (1.3-2.1-fold vs. daytime basal value), with a maximum at the end of the dark period and a minimum between noon and 4:00 p.m. 5D-III did not exhibit circadian patterns of variation in any of the brain tissues investigated. Our results disclose circadian rhythms of 5'D-II activity and thyroid hormone concentrations in discrete brain regions of rats entrained to a regular 12:12-h light-dark cycle and reveal that, in the rat CNS, T3 biosynthesis is activated during the dark phase of the photoperiod. For all parameters under investigation, the patterns of variation observed were in part regionally specific, indicating that different regulatory mechanisms may be involved in generating the observed rhythms.

Effects of lithium and carbamazepine on thyroid hormone metabolism in rat brain.

The effects of lithium (LI) and carbamazepine (CBM) on thyroid hormone metabolism were investigated in 11 regions of the brain and three peripheral tissues in rats decapitated at three different times of day (4:00 A.M., 1:00 P.M., and 8:00 P.M.). Interest was focused on the changes in the two enzymes that catalyze: (1) the 5'deiodination of T4 to the biologically active T3, i.e., type II 5'deiodinase (5'D-II) and (2) the 5 (or inner-ring) deiodination of T3 to the biologically inactive 3'3-T2, i.e., type III 5 deiodinase (5D-III). A 14-day treatment with both LI and CBM induced significant reductions in 5D-III activity. However, 5'D-II activity was elevated by CBM and reduced by LI, both administered in concentrations leading to serum levels comparable with those seen in the prophylactic treatment of affective disorders. The effects were dose dependent, varied according to the region of the brain under investigation, and strongly depended on the time of death within the 24-hour rhythm. The consequences of these complex effects of LI and CBM on deiodinase activities for thyroid hormone function in the CNS and also their possible involvement in the mechanisms underlying the mood-stabilizing effects of both LI and CBM remain to be investigated.

Serum concentrations of thyroid hormones in patients with nonseasonal affective disorders during treatment with bright and dim light.

Serum concentrations of thyroxine (T4), triiodothyronine (T3), and thyrotropine were measured in 34 patients with nonseasonal affective disorders before and after 1 week of light treatment. Nineteen of these patients received bright white light (2500 lx) and 15 dim red light (50 lx) for 2 hours daily in the mornings over a 1-week period. Slight but significant reductions in the rating scores for the depressive symptomatology were found for both the bright-and dim-light groups, but there were no significant differences between the two groups. The improvement is thus most likely a placebo effect. Surprisingly, the small changes in the severity of the depressive symptoms in the group as a whole were significantly correlated to the changes in the serum levels of T4 during the weeks of bright- and dim-light treatment, respectively. The more a patient improved, the further his or her T4 level fell and vice versa. The fluctuations in the concentrations of T4 during light treatment were significantly greater in the depressed patients than in a group of 12 healthy controls who also received bright or dim light, whereas the changes in T3 were significantly smaller than those of the healthy controls. The pronounced fluctuations in T4 levels were probably not secondary to changes in mood. Rather, they are likely to reflect changes in tissue (intracellular) metabolism of T4, which may be involved in the mechanisms underlying the fluctuations in mood in these patients.

Phenolic and tyrosyl ring iodothyronine deiodination and thyroid hormone concentrations in the human central nervous system.

In the present study we investigated the biochemical properties of in vitro phenolic (5'D) and tyrosyl (5D) ring deiodination and the tissue concentrations of T4, T3, and rT3 in adult human central nervous system (CNS) tissue. All samples were obtained from nontumoral tissue at autopsy (n = 6) or neurosurgical operation (n = 5). Both phenolic and tyrosyl ring deiodinase activities were demonstrable in all samples obtained intraoperatively, whereas only tyrosyl ring deiodination was evident in the tissues obtained postmortem. The phenolic ring deiodination pathway corresponded to the type II 5'-deiodinase isoenzyme with regard to its high affinity for T4 and rT3 (Km = 2.2 and 2.4 nmol/L, respectively), its insensitivity to 6-propyl-n-2-thiouracil (PTU), and the sequential reaction mechanism. No PTU-sensitive 5'-deiodination of rT3 was demonstrable. Tyrosyl ring deiodination of both T4 and T3 showed typical type III 5D kinetics (Ka, 6.5 nmol/L for T4 and 3.4 nmol/L for T3) and was PTU insensitive. Nanomolar concentrations of tissue T4, T3, and rT3 were detected in samples obtained both intraoperatively and postmortem. They were very similar to the absolute values of the apparent Km for T4, T3, and rT3 in the phenolic and tyrosyl ring deiodination pathways. In conclusion, we have demonstrated the coexistence of both phenolic and tyrosyl ring deiodinase activities in the human CNS. Their kinetic characteristics, substrate specificity, and reaction mechanisms are very similar to the corresponding type II 5'- and type III 5-iodothyronine deiodinase activities in rat brain. In contrast to the findings in the rat CNS, no PTU-sensitive phenolic ring deiodinase (i.e. type I 5'D) activity was found in the human CNS. This may explain the relatively high tissue concentrations of rT3.