Thyroid hormone action on glucose and energy metabolism in vivo studies

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。我们之前发现，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. We previously 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 developing and implementing a portfolio of clinical protocols aimed to characterize in vivo the role of the peripheral metabolism of thyroid hormone and its role in modulating the energy and glucose metabolism. Specifically, the following protocols have been implemented: 05-DK-0119 Peripheral Thyroid Hormone Conversion and Glucose and Energy Metabolism. This clinical protocol aimed to characterize in vivo the role of the peripheral metabolism of thyroid hormone with respect to glucose and energy metabolism is designed as a double blind, cross over study in which hypothyroid patients are treated either with T4 or T3 and after reaching a stable replacement dose, are admitted to the Metabolic Unit of the Clinical Center for a detailed evaluation of the energy and glucose homeostasis. Presently twelve patients have completed both phases of the study. The data obtained from this protocol have allowed us to characterize the pharmaco-equivalency of levothyroxine and liothyronine. This information is of clinical relevance since the preparation for the treatment of differentiated thyroid cancer is based on the substitution of liothyronine for levothyroxine. The data obtained form this protocol allow an accurate substitution of the thyroid hormone replacement, thus minimizing the discomfort and the potential risks associated with over- or under-replacement. The data have been presented in a manuscript entitled: "The pharmacodynamic equivalence of levothyroxine and liothyronine. A randomized, double blind, cross-over study in thyroidectomized patients" recently accepted for publication in Clinical Endocrinology. We are currently analyzing the differences between the two thyroid hormone formulations at the target-organ level. 06-DK-0133 Thyroid hormone-induced lipolysis: an in vivo microdialysis study. This clinical protocol is aimed to study, by exploiting the microdialysis technique, the pharmacological action of thyroid hormone on the adipose tissue and to study in vivo the action of the deiodinases. The study is subdivided in four phases. Healthy volunteers are currently recruited and it is expected that the collection of the data will be completed by FY 10. 07-DK-0202 Thyroid hormones homeostasis and energy metabolism changes during exposure to cold temperature in humans. This clinical protocol is aimed to study in vivo, by taking advantage of the newly opened respiratory chamber in the Metabolic Unit of the Clinical Center, the changes of circulating thyroid hormones during exposure to mild changes in environmental temperature. The first phase of the study has been completed and 25 volunteers have successfully completed the study. A manuscript describing the changes in energy expenditure, substrate utilization and hormonal changes is currently being completed. The results obtained thus far have prompted us to request an amendment to the protocol in order to extend the recruitment to obese and elderly individuals, and to perform PET studies in order to analyze the physiological role of brown adipose tissue in the cold-induced thermogenesis. 07-DK-0219 A Nutrigenomics Intervention for the Study of the Role of Dietary Sitosterol on Lipid, Glucose and Energy Metabolism. This is a nutrigenomics intervention on ABCG8 mutation carriers and sex-matched unaffected siblings aimed to study the effects of the interaction between modifications of ABCG8 gene mutations and plant sterol dietary content. We hypothesize that carriers of the ABCG8 gene mutation will further improve metabolic syndrome indices when challenged with a high-sitosterol diet, and will regress toward the non-carrier controls when treated with a low-sitosterol diet. This study is conducted in the Old Order Amish population of Lancaster Co. PA, a founder population with a high prevalence of ABCG8 mutations. Currently three sib-pairs have completed the first phase of the study. An amendment requesting the extension of the recruitment to no-sibling has been recently approved by both NIDDK-NIAMS IRB and University of Maryland IRB. We are confident that this change to the protocol will allow an increase in the accrual rate of study subjects, allowing the completion of the study. 08-DK-0165 Thyroid hormones homeostasis and energy metabolism changes during stimulation of endogenously secreted bile acids (BAs). In vitro and animal data indicate that the bile acids activate in a endocrine fashion the conversion of T4 to T3 ultimately leading to an increase in energy expenditure. This translational protocol is aimed to study in healthy volunteers the role of macronutrients and bile acids in the thermic effects of food. The protocol has being approved by the NIDDK/NIAMS IRB and currently 16 healthy volunteers have successfully completed the study. 08-DK-0058 Pharmacogenomic Response to Thyrotropin-Releasing Hormone Stimulation in Healthy Volunteers: The Influence of a Common Type 2 Deiodinase Genetic Polymorphism on Serum T3. Our data obtained form McCune-Albright Syndrome patients clearly indicate that intra-thyroidal conversion of T4 in T3 occurs upon activation of the cAMP pathway. We are thus exploiting this pathway using a pharmacogenomic study design to assess in vivo the effects of a common polymorphism of the D2 (Thr92Ala) by analyzing the differences in T3 levels upon TRH-stimulated raise in TSH in individuals carriers of the three genotypes (Thr/Thr, Thr/Ala, and Ala/Ala). Currently 39 out of the projected 45 study volunteers have successfully completed the study. We are confident that this study will be completed by the end of FY10.