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G A C van Haasteren, E Sleddens-Linkels, H van Toor, W Klootwijk, F H de Jong, T J Visser and W J de Greef


We investigated the effects of diabetes mellitus on the hypothalamo-hypophysial-thyroid axis in male (R×U) F1 and R-Amsterdam rats, which were found to respond to streptozotocin (STZ)-induced diabetes mellitus with no or marked increases, respectively, in plasma corticosterone. Males received STZ (65 mg/kg i.v.) or vehicle, and were killed 1, 2 or 3 weeks later. At all times studied, STZ-induced diabetes mellitus resulted in reduced plasma TSH, thyroxine (T4) and 3,5,3′-tri-iodothyronine (T3). Since the dialyzable T4 fraction increased after STZ, probably as a result of decreased T4-binding prealbumin, plasma free T4 was not altered during diabetes. In contrast, both free T3 and its dialyzable fraction decreased during diabetes, which was associated with an increase in T4-binding globulin. Hepatic activity of type I deiodinase decreased and T4 UDP-glucuronyltransferase increased after STZ treatment. Thus, the lowered plasma T3 during diabetes may be due to decreased hepatic T4 to T3 conversion.

Median eminence content of TRH increased after STZ, suggesting that hypothalamic TRH release is reduced during diabetes and that this is not caused by impaired synthesis or axonal transport of TRH to the median eminence. Hypothalamic proTRH mRNA did not change in diabetic (R×U) F1 rats during the period of observation, but was lower in R-Amsterdam rats 3 weeks after STZ. Similarly, pituitary TSH and TSHβ mRNA had decreased in R-Amsterdam rats by 1 week after STZ treatment, but did not change in (R×U) F1 rats. The difference between the responses in diabetic R-Amsterdam and (R×U) F1 rats may be explained on the basis of plasma corticosterone levels which increased in R-Amsterdam rats only. Hypothalamic TRH content was not affected by diabetes mellitus, but the hypothalami of diabetic rats released less TRH in vitro than those of control rats. Moreover, insulin had a positive effect on TRH release in vitro.

In conclusion, the reduced hypothalamic TRH release during diabetes is probably not caused by decreases in TRH synthesis or transport to the median eminence, but seems to be due to impaired TRH release from the median eminence which may be related to the lack of insulin. Inhibition of proTRH and TSHβ gene expression in diabetic R-Amsterdam rats is not a primary event but appears to be secondary to enhanced adrenal activity in these animals during diabetes.

Journal of Endocrinology (1997) 153, 259–267

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G Schreiber

In larger mammals, thyroid hormone-binding plasma proteins are albumin, transthyretin (TTR) and thyroxine (T4)-binding globulin. They differ characteristically in affinities and release rates for T4 and triiodothyronine (T3). Together, they form a 'buffering' system counteracting thyroid hormone permeation from aqueous to lipid phases. Evolution led to important differences in the expression pattern of these three proteins in tissues. In adult liver, TTR is only made in eutherians and herbivorous marsupials. During development, it is also made in tadpole and fish liver. More intense TTR synthesis than in liver is found in the choroid plexus of reptilians, birds and mammals, but none in the choroid plexus of amphibians and fish, i.e. species without a neocortex. All brain-made TTR is secreted into the cerebrospinal fluid, where it becomes the major thyroid hormone-binding protein. During ontogeny, the maximum TTR synthesis in the choroid plexus precedes that of the growth rate of the brain and occurs during the period of maximum neuroblast replication. TTR is only one component in a network of factors determining thyroid hormone distribution. This explains why, under laboratory conditions, TTR-knockout mice show no major abnormalities. The ratio of TTR affinity for T4 over affinity for T3 is higher in eutherians than in reptiles and birds. This favors T4 transport from blood to brain providing more substrate for conversion of the biologically less active T4 into the biologically more active T3 by the tissue-specific brain deiodinases. The change in affinity of TTR during evolution involves a shortening and an increase in the hydrophilicity of the N-terminal regions of the TTR subunits. The molecular mechanism for this change is a stepwise shift of the splice site at the intron 1/exon 2 border of the TTR gene. The shift probably results from a sequence of single base mutations. Thus, TTR evolution provides an example for a molecular mechanism of positive Darwinian evolution. The amino acid sequences of fish and amphibian TTRs are very similar to those in mammals, suggesting that substantial TTR evolution occurred before the vertebrate stage. Open reading frames for TTR-like sequences already exist in Caenorhabditis elegans, yeast and Escherichia coli genomes.

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E M de Vries, H C van Beeren, M T Ackermans, A Kalsbeek, E Fliers and A Boelen

( Boelen et al . 2006 ). Whether NTIS is an adaptive or maladaptive response is still a matter of debate. Fasting leads to a central downregulation of the HPT axis, characterized by increased type 2 deiodinase expression in hypothalamic tanycytes which

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Nicolás Gigena, Vanina A Alamino, María del Mar Montesinos, Magalí Nazar, Ruy A Louzada, Simone M Wajner, Ana L Maia, Ana M Masini-Repiso, Denise P Carvalho, Graciela A Cremaschi and Claudia G Pellizas

). It is noteworthy that the action of TH requires the proper interplay among cellular TH transporters, TH deiodinases and TRs expression ( Williams & Bassett 2011 , Kwakkel et al . 2014 ). The uptake–efflux of THs by target cells is facilitated by

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Andréa Gonçalves Trentin

the brain derives from the local conversion of thyroxine (T4) ( Crantz et al. 1982 , Courtin et al. 1986 ), catalyzed by a cAMP-inducible membrane-bound enzyme, the type II iodothyronine 5′-deiodinase (D2) ( Courtin et al. 1988 , Leonard 1988

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Anita Boelen, Anne H van der Spek, Flavia Bloise, Emmely M de Vries, Olga V Surovtseva, Mieke van Beeren, Mariette T Ackermans, Joan Kwakkel and Eric Fliers

preferentially transports T 3 instead of T 4 and is expressed in kidney, liver and muscle ( Visser et al . 2011 ). Once transported into the cell, thyroid hormones can be metabolised by outer or inner ring deiodination through the iodothyronine deiodinases, a

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Francisco J Arjona, Luis Vargas-Chacoff, María P Martín del Río, Gert Flik, Juan M Mancera and Peter H M Klaren

reaction is catalyzed by iodothyronine deiodinases, a family of selenoenzymes, of which three types exist. Deiodinases type 1 (D1) and type 2 (D2) catalyze the outer ring deiodination (ORD, or 5′-deiodination) pathway that converts the prohormone T 4 to T

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Stijn L J Van Herck, Stijn Geysens, Edward Bald, Grazyna Chwatko, Evelyne Delezie, Elham Dianati, R G Ahmed and Veerle M Darras

,5,3′-triiodothyronine (T 3 ) availability, and it may not yet be able to compensate for a reduced TH supply by an increase in type 2 iodothyronine deiodinase (D2) activity as observed in the adult brain ( Ruiz de Ona et al . 1988 , Van Herck et al . 2012 ). Apart

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Colin Farquharson

predominant thyroid hormone secreted by the thyroid gland before it is activated by its conversion into T 3 by the types 1 and 2 iodothyronine deiodinase enzymes (D1 and D2). This conversion produces about 80% of the active T 3 hormone present within the

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Marian Ludgate

could be verified by measuring deiodinase transcripts and enzyme activity in the peripheral tissues of the thyroidectomised rodents compared with euthyroid controls. Their second, and more controversial, conclusion is that the low levels of thyroid