Effects of the conversion of thyroid hormone on glucose

摘要：甲状腺激素在几乎所有器官的发育和功能中起着重要的调节作用，其稳态是由一个高度调节的多步骤冗余系统维持的。甲状腺激素的外周代谢通过调节循环和细胞内活性激素T3的水平，是激素作用的重要组织特异性受体前调节剂。脱碘酶是将原激素T4转化为活性激素T3或转化为代谢不活跃的rT3的硒酶。最近，我们发现2型去碘素基因（Thr92Ala）的常见多态性与葡萄糖处理减少有关，并且在先前描述的失活β -3肾上腺素能受体多态性存在的情况下，与体重指数虽小但显著增加有关。有趣的是，这种多态性并不影响身体活跃的创始人群Old Order Amish的胰岛素抵抗指数，这表明基因-环境相互作用。我们推测Thr92Ala多态性会产生一种缺陷酶，从而导致细胞内T4到T3的转化减少，最终导致能量消耗减少和胰岛素依赖性葡萄糖转运体-4的转录受损，该基因受甲状腺激素调节。

Summary: Thyroid hormone plays an important regulatory role in the development and function of virtually all organs and its homeostasis is maintained by a highly regulated, multi-step redundant system. The peripheral metabolism of thyroid hormone, by regulating the circulating and intracellular levels of the active hormone T3, represents an important tissue-specific pre-receptor modulator of the hormonal action. The deiodinases are selenoenzymes which convert the pro-hormone T4 into its active hormone T3 or into the metabolically inactive rT3. Recently, we discovered that a common polymorphism of the type 2 deiodianse gene (Thr92Ala) associates with decreased glucose disposal and, in the presence of a previously described inactivating beta-3 adrenergic receptor polymorphism, with a small but significant increase in body mass index. Interestingly, this polymorphism does not affect indices of insulin resistance in a physically active founder population, the Old Order Amish, suggesting a gene-environment interaction. We speculated that the Thr92Ala polymorphism generates a defective enzyme thus leading to a decrease intracellular conversion of T4 to T3, ultimately leading to reduced energy expenditure and impaired transcription of the insulin-dependent glucose transporter-4, whose gene is thyroid hormone-regulated. During this year we have focused our efforts in defining the role of the peripheral conversion of thyroid hormone in the pathogenesis of insulin resistance and obesity. We further characterized the enzymatic properties of the Thr92Ala variant and discovered that the polymorphism impairs the protesaome-induced degradation of the enzyme. We are now performing in vitro reconstruction experiments to further characterize the protein-protein interaction leading to this phenomenon. During this year we have also devoted efforts toward the characterization of another naturally occurring polymorphism in the 5? UTR region of the human type-II deiodinase gene (258 A/G). Our data indicate that the naturally occurring polymorphism reduces the affinity for a repressor thus increasing the transcription rate of the gene. These data are in keeping with in vivo observations made by another group. In order to characterize in vivo the role of the peripheral metabolism of thyroid hormone with respect to glucose and energy metabolism, we have generated a clinical protocol aimed to administer in double blind, cross over fashion either T4 or T3 to thyroidectomized patients (05-DK-0119). Recruitment of patients started in July 05 and currently 5 patients (10% of the projected study population) have been randomized. This approach, will allow us to define in vivo the role of the peripheral conversion of thyroid hormone in the maintenance of glucose and energy metabolism. Finally, a clinical protocol aimed to characterize in vivo the action of thyroid hormone and the role of local conversion of thyroid hormone in adipose tissue by means of microdialysis is currently under scientific review. Normal volunteer will undergo adipose tissue microdialysis and various concentrations of either T4 or T3 will be infused in the subcutaneous adipose tissue. Glycerol concentration in the effluent fluid will be considered as readout for thyroid hormone-induced lipolyisis.