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Free access

T Mokuno, K Uchimura, R Hayashi, N Hayakawa, M Makino, M Nagata, H Kakizawa, Y Sawai, M Kotake, N Oda, A Nakai, A Nagasaka and M Itoh

The deterioration of glucose metabolism frequently observed in hyperthyroidism may be due in part to increased gluconeogenesis in the liver and glucose efflux through hepatocyte plasma membranes. Glucose transporter 2 (GLUT 2), a facilitative glucose transporter localized to the liver and pancreas, may play a role in this distorted glucose metabolism. We examined changes in the levels of GLUT 2 in livers from rats with l-thyroxine-induced hyperthyroidism or methimazole-induced hypothyroidism by using Western blotting to detect GLUT 2. An oral glucose tolerance test revealed an oxyhyperglycemic curve (impaired glucose tolerance) in hyperthyroid rats (n=7) and a flattened curve in hypothyroid rats (n=7). GLUT 2 levels in hepatocyte plasma membranes were significantly increased in hyperthyroid rats and were not decreased in hypothyroid rats compared with euthyroid rats. The same results were obtained with a densitometric assay. These findings suggest that changes in the liver GLUT 2 concentration may contribute to abnormal glucose metabolism in thyroid disorders.

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Sisi Luan, Wenkai Bi, Shulong Shi, Li Peng, Zhanbin Li, Jie Jiang, Ling Gao, Yifeng Du, Xu Hou, Zhao He and Jiajun Zhao

Subclinical hyperthyroidism, a condition characterized by decreased thyroid-stimulating hormone (TSH) and normal concentration of thyroid hormone, is associated with an elevated risk for cognitive impairment. TSH is the major endogenous ligand of the TSH receptor (TSHR) and its role is dependent on signal transduction of TSHR. It has not, however, been established whether TSHR signaling is involved in the regulation of cognition. Here, we utilized Tshr knockout mice and found that Tshr deletion led to significantly compromised performance in learning and memory tests. Reduced dendritic spine density and excitatory synaptic density as well as altered synaptic structure in CA1 subfield of the hippocampus were also noted. Furthermore, the synapse-related gene expression was altered in the hippocampus of Tshr -/- mice. These findings suggest that TSHR signaling deficiency impairs spatial learning and memory, which discloses a novel role of TSHR signaling in brain function.

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T Mano, K Iwase, Y Sawai, N Oda, Y Nishida, T Mokuno, Y Itoh, M Kotake, R Masunaga, A Nakai, T Tujimura, A Nagasaka and H Hidaka

Abstract

To investigate the effect of thyroid hormone on cardiac muscle dysfunction in hyper- and hypothyroid states, we evaluated cyclic 3′, 5′-nucleotide metabolism by measuring cyclic 3′, 5′-nucleotide phosphodiesterase activity and calmodulin concentrations in the cardiac muscles of hyper- and hypothyroid rats.

Cyclic AMP (cAMP) concentration was significantly high in the cardiac muscle of hyperthyroid rats and low in that from hypothyroid rats compared with control rats. Cyclic AMP and cyclic GMP phosphodiesterase activities were significantly decreased in the soluble fraction of cardiac muscle from hyperthyroid rats and markedly increased in this fraction in hypothyroid rats compared with normal animals. Calmodulin concentration was high in hyperthyroid and low in hypothyroid rats.

It was concluded from these findings that low cAMP-phosphodiesterase activity might, in part, bring about the high concentration of cAMP. Calmodulin was sigificantly high in the cardiac muscle of hyperthyroid rats and the reverse was the case in hypothyroid rats compared with normal rats. The implication is that, in hyper- and hypothyroid states, these changes may play an important role in cardiac function via their effect on cyclic nucleotide and Ca2+ metabolism.

Journal of Endocrinology (1994) 143, 515–520

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Hans-Peter Holthoff, Kerstin Uhland, Gabor Laszlo Kovacs, Andreas Reimann, Kristin Adler, Clara Wenhart and Martin Ungerer

Graves’ disease is an autoimmune disorder, which is characterized by stimulatory antibodies targeting the human thyrotropin receptor (TSHR), resulting in hyperthyroidism and multiple organ damage. We systematically investigated mono- and dimeric fusion proteins of the A subunit of TSHR for efficacy to bind to the monoclonal patient antibody M22, to interact with Graves’ patient serum samples, and to impact on anti-TSHR antibody titers, hyperthyroidism, tachycardia and other in vivo read-outs in a long-term mouse model of Graves’ disease induced by immunization with a recombinant adenovirus encoding TSHR A. Binding assays and functional measurements of TSHR-dependent cAMP formation showed binding of monomeric TSHR-His and dimeric TSHR-Fc to the anti-TSHR antibody M22 at low effective concentrations (EC50 of 5.7 nmol/L and 8.6 nmol/L) and inhibition of the effects of this antibody at high efficiencies (IC50-values of 16–20 nmol/L). Both proteins also block the effects of polyclonal anti-TSHR antibodies occurring in Graves’ patient sera with somewhat lower average efficiencies (mean IC50 values of 29 nmol/L and 68 nmol/L). However, in vivo characterization of epicutaneous patch administrations of TSHR-Fc at doses of 0.3 and 0.6 mg/kg body weight in a murine Graves’ disease model did not result in any improvement of disease parameters. High affinity binding of TSHR-Fc to pathological anti-TSHR antibodies was not matched by efficacy to improve Graves’ disease parameter in a long-term mouse model.

Free access

Beate Karges, Gerd Krause, Janos Homoki, Klaus-Michael Debatin, Nicolas de Roux and Wolfram Karges

Mutations of the human thyrotrophin receptor (TSH-R) are a cause of thyroid adenomas and hyperthyroidism. Here we study mechanisms of receptor activation in a genomic TSH-R variant V509A located in transmembrane helix (TMH) 3, which we identify in a family with congenital hyperthyroidism, multiple adenomas and follicular thyroid cancer. Using molecular modelling and dynamic simulation, we predicted the release of amino acid residue A593 (located opposite in domain TMH5) from a tight ‘knob-and-hole’ interaction with TMH3, physiologically constrained in the native receptor state by the bulky side chain of V509. To experimentally validate this concept, we generated mutant TSH-R expression constructs for functional in vitro studies. TSH-R mutant V509A showed a 2.8-fold increase in basal cAMP production, confirming constitutive TSH-R activation. The addition of a second site suppressor mutant A593V to TSH-R V509A resulted in the normalization of basal cAMP release, and the dose-responsiveness to TSH ligand was maintained. These data thus demonstrate that TSH-R V509A activation is caused by the release of TMH3–TMH5 interhelical constraints, while the native TSH-R conformation is re-stabilized by the introduction of a spacious valine residue at position 593. In conclusion, we delineate a novel mechanism of constitutive TSH-R activation, leading to thyroid hyperfunction and neoplasia.

Open access

Shuang-Xia Zhao, Shanli Tsui, Anthony Cheung, Raymond S Douglas, Terry J Smith and J Paul Banga

The TSH receptor (TSHR) is the critical target for antibody production in Graves' disease (GD). Insulin-like growth factor 1 receptor (IGF1R) has been proposed as a second autoantigen in complications of GD such as orbitopathy. We attempted to induce orbital tissue remodeling in mice undergoing immunizations with plasmids encoding TSHR and IGF1R delivered by in vivo skeletal muscle electroporation, a procedure known to give a sustained, long-term antibody response. Female BALB/c mice were challenged with TSHR A-subunit or IGF1Rα subunit plasmid by injection and electroporation. Mice challenged with TSHR A-subunit plasmid resulted in high frequency (75%) of hyperthyroidism and thyroid-stimulating antibodies. But strikingly, immunization with TSHR A-subunit plasmid also elicited antibody to IGF1Rα subunit. Mice challenged in the same manner with IGF1Rα subunit plasmid produced strong antibody responses to IGF1R, but did not undergo any changes in phenotype. Simultaneous challenge by double antigen immunization with the two plasmids in distant anatomical sites reduced the incidence of hyperthyroidism, potentially as a consequence of antigenic competition. Thyroid glands from the TSHR A-subunit plasmid-challenged group were enlarged with patchy microscopic infiltrates. Histological analysis of the orbital tissues demonstrated moderate connective tissue fibrosis and deposition of Masson's trichrome staining material. Our findings imply that immunization with TSHR A-subunit plasmid leads to generation of IGF1R antibodies, which together with thyroid-stimulating antibodies may precipitate remodeling of orbital tissue, raising our understanding of its close association with GD.

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T Mano, K Iwase, I Yoshimochi, Y Sawai, N Oda, Y Nishida, T Mokuno, M Kotake, A Nakai, N Hayakawa, R Kato, A Nagasaka and H Hidaka

Abstract

Hyper- and hypothyroid states occasionally induce skeletal muscle dysfunction i.e. periodic paralysis and thyroid myopathy. The etiology of these diseases remains unclear, but several findings suggest that the catecholamine-β-receptor-cAMP system or other messenger systems are disturbed in these diseases. In this context, we evaluated changes in the cyclic 3′,5′-nucleotide metabolic enzyme, cyclic 3′,5′-nucleotide phosphodiesterase (PDE) and calmodulin concentrations in skeletal muscles of hyper- and hypothyroid rats.

Activities of cyclic AMP-PDE were low in skeletal muscle both from hyper- and hypothyroid rats, and calmodulin concentration was high in hyperthyroid and low in hypothyroid rats, as compared with normal rats. DE-52 column chromatographic analysis showed that the cGMP hydrolytic activity in peak I and the cAMP hydrolytic activity in peak II were decreased in hypothyroid rats, whereas cAMP hydrolytic activity in peak III was unchanged. The cAMP hydrolytic activity in peak III was decreased in hyperthyroid rats, but the activities in peaks I and II were unchanged. These findings indicate that cAMP and calmodulin may have some role in skeletal muscle function in the hyperthyroid state, and that cAMP and calmodulin-dependent metabolism may be suppressed in the hypothyroid state.

Journal of Endocrinology (1995) 146, 287–292

Free access

Takao Ando, Rauf Latif and Terry F Davies

The post-translational processing of the TSH receptor (TSHR) includes intra-molecular cleavage with the loss of a 50 amino acid ectodomain region and the formation of two subunits (α and β), followed by likely α subunit shedding. TSHR antibodies (TSHR-Abs), which are directed at the ectodomain, may influence thyroid function by stimulating or inhibiting TSHR signaling or may bind without any such influence (the neutral group of antibodies). When we examined the characteristics of a series of monoclonal TSHR-Abs, we found that many were able to inhibit receptor cleavage and enhance TSHR expression. This was especially apparent with the neutral type of TSHR-Abs directed to the cleaved region of the ectodomain (aa 316–366). Indeed, such inhibition appeared to be epitope dependent with TSHR-Abs directed to regions after residues 335–354 showing no such activity. We propose that this aberrant process, whereby TSHR-Abs influence antigen processing, is a novel mechanism for the maintenance and exacerbation of autoimmune thyroid disease.

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G. E. BEAUMONT, E. C. DODDS and J. D. ROBERTSON

The object of the experiments described was to determine whether the decalcification occurring in the human skeleton in thyrotoxicosis can be attributed to thyroxine or to some other factor.

A probable relationship between the thyroid gland and calcium and phosphorus metabolism has been suggested by many workers who have based their evidence on clinical grounds, the radiological study of bones, biochemical analyses on blood-serum, calcium and phosphorus balance experiments, and finally the post-mortem appearance of the skeleton.

Evidence of Decalcification in Thyrotoxicosis

Clinical evidence

Von Jaksch & Rotky [1908–9] reported softening and bending of the bones in a girl of 20 suffering from hyperthyroidism, and Bernhardt [1927] observed a similar case. These authors suggested that the osteomalacia resulted from a decalcification of the skeleton, and this was attributed to thyrotoxicosis.

X-ray appearance of bones

Kummer [1917] appears to be among the first observers to draw attention to the occurrence of

Free access

SM van der Heide, BJ Joosten, ME Everts and PH Klaren

We have investigated the hypothesis that uridine 5'-diphosphate (UDP)-glucuronyltransferases (UGTs) and beta-glucuronidase are jointly involved in a mechanism for the storage and mobilization of iodothyronine metabolites in liver, kidney, heart and brain. Specifically, we predicted UGT activities to decrease and increase respectively, and beta-glucuronidase activity to increase and decrease respectively in hypo- and hyperthyroidism. To this end we have studied the effects of thyroid status on the activities of different enzymes involved in thyroid hormone metabolism in liver, kidney, heart and brain from adult rats with experimentally induced hypo- and hyperthyroidism. We used whole organ homogenates to determine the specific enzyme activities of phenol- and androsteron-UGT, beta-glucuronidase, as well as iodothyronine deiodinase types I and II. Deiodinase type I activities in liver and kidney were decreased in hypothyroid animals and, in liver only, increased in hyperthyroidism. Deiodinase type II activity was increased in hyperthyroid rat kidney only. Interestingly, in the heart, deiodinase type I-specific activity was increased fourfold, although the increase was not statistically significant. Cardiac deiodinase type I activity was detectable but not sensitive to thyroid status. Hepatic phenol-UGT as well as androsteron-UGT activities were decreased in hypothyroid rats, with specific androsteron-UGT activities two to three orders of magnitude lower than phenol-UGT activities. Both UGT isozymes were well above detection limits in heart, but appeared to be insensitive to thyroid status. In contrast, cardiac beta-glucuronidase activity decreased in hypothyroid tissue, whereas the activity of this enzyme in the other organs investigated did not change significantly.In summary, cardiac beta-glucuronidase, albeit in low levels, and hepatic phenol-UGT activities were responsive only to experimental hypothyroidism. Although a high basal activity of the pleiotropic beta-glucuronidase masking subtle activity changes in response to thyroid status cannot be ruled out, we conclude that hepatic, renal and cardiac UGT and beta-glucuronidase activities are not regulated reciprocally with thyroid status.