Effects of the conversion of thyroid hormone on glucose

甲状腺激素转化对血糖的影响

• 批准号: 7337587
• 负责人: FRANCESCO S CELI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7337587
• 关键词: Effects; conversion; thyroid; hormone; glucose

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. Our effort is now devoted to the identification and characterization of the type-2 deiodinase repressor. 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 8 patients have been randomized, two have competed the study and other thre have completed the first admission. 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 has been approved (06-DK-0133). 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.

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，其动态平衡是由一个高度调节的、多步骤冗余的系统维持的。甲状腺激素的外周代谢，通过调节活性激素T3的循环和细胞内水平，代表了激素作用的重要的组织特异性受体前调节器。脱碘酶是一种硒酶，它能将原激素T4转化为活性激素T3，或转化为代谢不活跃的RT3。最近，我们发现2型去碘基因(Thr92Ala)的一个常见的多态性与糖代谢减少有关，并且在先前描述的β-3肾上腺素能受体失活的情况下，与体重指数小幅但显著的增加有关。有趣的是，这种多态并不影响体力活动的创始人群体--阿米什人的胰岛素抵抗指数，这表明这是一种基因-环境相互作用。我们推测Thr92Ala基因多态产生一种缺陷酶，从而导致T4到T3的细胞内转换减少，最终导致能量消耗减少和胰岛素依赖的葡萄糖转运蛋白-4转录受损，其基因受甲状腺激素调节。 在这一年里，我们致力于确定甲状腺激素的外周转化在胰岛素抵抗和肥胖发病机制中的作用。我们进一步鉴定了Thr92Ala变异体的酶性质，发现该多态性削弱了蛋白质组诱导的酶的降解。我们现在正在进行体外重建实验，以进一步表征导致这一现象的蛋白质-蛋白质相互作用。 在这一年里，我们还致力于描述另一种自然发生的5？人类II型脱碘酶基因非编码区(258A/G)。我们的数据表明，自然发生的多态降低了对抑制物的亲和力，从而提高了基因的转录速率。这些数据与另一个小组的活体观察结果是一致的。我们现在致力于2型脱碘酶抑制因子的鉴定和特性研究。 为了在体内研究甲状腺激素的外周代谢在葡萄糖和能量代谢方面的作用，我们制定了一个临床方案，旨在以双盲、交叉方式给甲状腺切除患者T4或T3(05-DK-0119)。从2005年7月开始招募患者，目前已随机抽取8名患者，2名患者参加了研究，其他3名患者完成了首次入院。这一方法将使我们能够在体内确定甲状腺激素的外周转换在维持葡萄糖和能量代谢中的作用。 最后，一项旨在通过微透析在体内表征甲状腺激素的作用和脂肪组织中甲状腺激素局部转化作用的临床方案已经获得批准(06-DK-0133)。正常志愿者将接受脂肪组织微透析，皮下脂肪组织将注入不同浓度的T4或T3。流出液中的甘油浓度将被认为是甲状腺激素诱导的脂肪分解的读数。