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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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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


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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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


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

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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.

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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

Alicia J Klecha, Ana M Genaro, Gabriela Gorelik, María Laura Barreiro Arcos, Dafne Magalí Silberman, Mariano Schuman, Silvia I Garcia, Carlos Pirola and Graciela A Cremaschi

Thyroid hormones play critical roles in differentiation, growth and metabolism, but their participation in immune system regulation has not been completely elucidated. Modulation of in vivo thyroid status was used to carry out an integrative analysis of the role of the hypothalamus–pituitary–thyroid (HPT) axis in T and B lymphocyte activity. The participation of the protein kinase C (PKC) signaling pathway and the release of some cytokines upon antigenic stimulation were analyzed. Lymphocytes from hyperthyroid mice displayed higher T-and B-cell mitogen-induced proliferation, and those from hypothyroid mice displayed lower T- and B-cell mitogen-induced proliferation, compared with euthyroid animals. Reversion of hypothyroid state by triiodothyronine (T3) administration recovered the proliferative responses. No differences were found in lymphoid subset balance. Both total PKC content and mitogen-induced PKC translocation were higher in T and B cells from hyperthyroid mice, and lower in cells from hypothyroid mice, compared with controls. Levels of thyroid-stimulating (TSH) and TSH-releasing (TRH) hormones were not directly related to lymphocyte proliferative responses. After immunization with sheep red blood cells (SRBCs) and re-stimulation, in vitro spleen cells from hyper- or hypothyroid mice showed, respectively, increased or decreased production of interleukin (IL)-2 and interferon (IFN)-γ cytokines. Additionally, an increase in IL-6 and IFN-γ levels was found in hyperthyroid cells after in vivo injection and in vitro re-stimulation with lipopolysaccharide (LPS).

Our results show for the first time a thyroid hormone-mediated regulation of PKC content and of cytokine production in lymphocytes; this regulation could be involved in the altered responsiveness to mitogen-induced proliferation of T and B cells. The results also confirm the important role that these hormones play in regulating lymphocyte reactivity.

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S. Iossa, G. Liverini and A. Barletta


The effects of thyroid state on liver mitochondrial protein mass was investigated in rats at 24 and 4 °C, as was oxidative phosphorylation using substrates which represent the final catabolic products of the metabolic fuels.

In rats at 24 °C, a significant increase in mitochondrial protein mass (about +40%) was observed only in hyperthyroid animals, while a significant increase due to cold exposure was found in hypothyroid (+ 45%) and euthyroid (+ 35%) rats.

In rats at 24 °C, hypothyroidism significantly decreased the oxidation of glutamate and palmitoyl carnitine but not of pyruvate, while hyperthyroidism only increased the oxidation of palmitoyl carnitine. On the other hand, exposure to cold significantly increased the oxidation of glutamate and pyruvate only in the presence of tri-iodothyronine.

Our results underline not only the fact that a simple and single hypothesis for thyroid effects cannot be adopted, but also that any study concerning oxidative metabolism should be carried out using different substrates and involving different pathways of oxidation.

Journal of Endocrinology (1991) 131, 67–73

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S. Iossa, G. Liverini and A. Barletta


We have examined the relationship between the changes in resting metabolic rate (RMR) and those in hepatic metabolism induced by hyperthyroidism and fasting for 24 h. We found that hyperthyroidism induced a significant increase in RMR, while fasting for 24 h reduced RMR in euthyroid but not in hyperthyroid rats. We have also measured oxygen consumption in isolated hepatocytes from euthyroid and hyperthyroid rats, fed or fasted for 24 h. Hyperthyroidism induced an increase in oxygen consumption in rat liver cells; fasting for 24 h increased respiratory rates in isolated liver cells from euthyroid but not from hyperthyroid rats.

The findings showed that hyperthyroidism and fasting for 24 h have opposite effects on RMR but similar effects on hepatic metabolism. The results also indicated that the increase in RMR found in hyperthyroid rats is partly due to an increase in hepatic metabolism, while no correlation exists between variations in resting and hepatic metabolism induced by 24-h fasting.

Journal of Endocrinology (1992) 135, 45–51

Free access

D Santos Ornellas, R Grozovsky, RC Goldenberg, DP Carvalho, P Fong, WB Guggino and M Morales

Thyroid hormones has its main role in controlling metabolism, but it can also modulate extracellular fluid Volume (ECFV) through its action on the expression and activity of Na(+) transporters. Otherwise, chloride is the main anion in the ECFV and the influence of thyroid hormones in the regulation of chloride transporters is not yet understood. In this work, we studied the effect of thyroid hormones in the expression of ClC-2, a cell Volume-, pH- and voltage-sensitive Cl(-) channel, in rat kidney. To analyze the modulation of ClC-2 gene expression by thyroid hormones, we used hypothyroid (Hypo) rats with or without thyroxine (T(4)) replacement and hyperthyroid (Hyper) rats as our experimental models. Total RNA was isolated and the expression of ClC-2 mRNA was evaluated by a ribonuclease protection assay, and/or semi-quantitative RT-PCR. Renal ClC-2 expression decreased in Hypo rats and increased in Hyper rats. In addition, semi-quantitative RT-PCR of different nephron segments showed that these changes were due exclusively to the modulation of ClC-2 mRNA expression by thyroid hormone in convoluted and straight proximal tubules. To investigate whether thyroid hormones action was direct or indirect, renal proximal tubule primary culture cells were prepared and subjected to different T(4) concentrations. ClC-2 mRNA expression was increased by T(4) in a dose-dependent fashion, as analyzed by RT-PCR. Western blotting demonstrated that ClC-2 protein expression followed the same profile of mRNA expression.

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Guillermo Vazquez-Anaya, Bridget Martinez, José G Soñanez-Organis, Daisuke Nakano, Akira Nishiyama and Rudy M Ortiz

Both hypothyroidism and hyperthyroidism are associated with glucose intolerance, calling into question the contribution of thyroid hormones (TH) on glucose regulation. TH analogues and derivatives may be effective treatment options for glucose intolerance and insulin resistance (IR), but their potential glucoregulatory effects during conditions of impaired metabolism are not well described. To assess the effects of thyroxine (T4) on glucose intolerance in a model of insulin resistance, an oral glucose tolerance test (oGTT) was performed on three groups of rats (n = 8): (1) lean, Long Evans Tokushima Otsuka (LETO), (2) obese, Otsuka Long Evans Tokushima Fatty (OLETF) and (3) OLETF + T4 (8.0 µg/100 g BM/day × 5 weeks). T4 attenuated glucose intolerance by 15% and decreased IR index (IRI) by 34% in T4-treated OLETF compared to untreated OLETF despite a 31% decrease in muscle Glut4 mRNA expression. T4 increased the mRNA expressions of muscle monocarboxylate transporter 10 (Mct10), deiodinase type 2 (Di2), sirtuin 1 (Sirt1) and uncoupling protein 2 (Ucp2) by 1.8-, 2.2-, 2.7- and 1.4-fold, respectively, compared to OLETF. Activation of AMP-activated protein kinase (AMPK) and insulin receptor were not significantly altered suggesting that the improvements in glucose intolerance and IR were independent of enhanced insulin-mediated signaling. The results suggest that T4 treatment increased the influx of T4 in skeletal muscle and, with an increase of DI2, increased the availability of the biologically active T3 to upregulate key factors such SIRT1 and UCP2 involved in cellular metabolism and glucose homeostasis.