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: 7153615
• 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/7153615
• 关键词: adipose tissue; bioenergetics; blood glucose; clinical research; enzyme mechanism; genetic polymorphism; glucose metabolism; glycerol; hormone metabolism; human subject; insulin sensitivity /resistance; iodide peroxidase; lipolysis; obesity; pathologic process; thyroid hormones; thyroxine; triiodothyronine

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.

摘要：甲状腺激素在几乎所有器官的发育和功能中发挥着重要的调节作用，其稳态由高度调节的多步骤冗余系统维持。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组织特异性前受体调节剂。脱碘酶是将激素原 T4 转化为其活性激素 T3 或代谢失活的 rT3 的硒酶。最近，我们发现 2 型脱碘酶基因 (Thr92Ala) 的常见多态性与葡萄糖处理减少相关，并且在存在先前描述的失活 β-3 肾上腺素受体多态性的情况下，与体重指数小幅但显着的增加有关。有趣的是，这种多态性并不影响身体活跃的创始人群体（旧秩序阿米什人）的胰岛素抵抗指数，这表明基因与环境之间存在相互作用。我们推测 Thr92Ala 多态性产生了一种有缺陷的酶，从而导致 T4 到 T3 的细胞内转化减少，最终导致能量消耗减少和胰岛素依赖性葡萄糖转运蛋白 4（其基因受甲状腺激素调节）的转录受损。 今年，我们的重点是确定甲状腺激素外周转化在胰岛素抵抗和肥胖发病机制中的作用。我们进一步表征了 Thr92Ala 变体的酶学特性，并发现多态性损害了蛋白酶体诱导的酶降解。我们现在正在进行体外重建实验，以进一步表征导致这种现象的蛋白质-蛋白质相互作用。 今年，我们还致力于表征 5?5 中另一种自然发生的多态性。人类 II 型脱碘酶基因的 UTR 区域 (258 A/G)。我们的数据表明，自然发生的多态性降低了阻遏物的亲和力，从而增加了基因的转录率。这些数据与另一组的体内观察结果一致。 为了表征体内甲状腺激素外周代谢相对于葡萄糖和能量代谢的作用，我们制定了一项临床方案，旨在以双盲、交叉方式向甲状腺切除患者施用 T4 或 T3 (05-DK-0119)。患者招募于 7 月 5 日开始，目前 5 名患者（占预计研究人群的 10%）已被随机分组​​。这种方法将使我们能够在体内定义甲状腺激素外周转化在维持葡萄糖和能量代谢中的作用。 最后，旨在通过微透析表征甲状腺激素体内作用以及甲状腺激素在脂肪组织中局部转化的作用的临床方案目前正在接受科学审查。正常志愿者将接受脂肪组织微透析，并将不同浓度的T4或T3注入皮下脂肪组织中。流出液中的甘油浓度将被视为甲状腺激素诱导的脂肪分解的读数。