Thyroid hormone action on glucose and energy metabolism in vivo studies

总结：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，其稳态由高度调节的多步冗余系统维持。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或转化为代谢失活的rT 3的硒酶。我们以前发现，2型脱碘酶基因（Thr 92 Ala）的常见多态性与葡萄糖处置减少有关，并且在存在先前描述的失活β-3肾上腺素能受体多态性的情况下，与体重指数的小但显著的增加有关。有趣的是，这种多态性并不影响指数的胰岛素抵抗的身体活动的创始人人口，旧秩序阿米什人，这表明基因环境相互作用。我们推测Thr 92 Ala多态性产生一种有缺陷的酶，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的转录受损，其基因是甲状腺激素调节的。 在这一年中，我们集中精力开发和实施一系列临床方案，旨在体内表征甲状腺激素外周代谢的作用及其在调节能量和葡萄糖代谢中的作用。 具体而言，已实施了以下协议： 05-DK-0119外周甲状腺激素转换和葡萄糖和能量代谢。本临床方案旨在体内表征甲状腺激素外周代谢在葡萄糖和能量代谢方面的作用，设计为双盲、交叉研究，其中甲状腺功能减退患者接受T4或T3治疗，达到稳定的替代剂量后，进入临床中心的代谢单位，对能量和葡萄糖稳态进行详细评价。目前，已有10名患者完成了研究的两个阶段。这项研究的初步结果已经在年度内分泌学会会议上发表。 06-DK-0133甲状腺激素诱导的脂解：体内微透析研究。本临床方案旨在通过利用微透析技术研究甲状腺激素对脂肪组织的药理作用，并研究体内脱碘酶的作用。研究分为四个阶段。目前正在招募健康志愿者，预计数据收集将在2009财年完成。 07-DK-0202人体暴露于低温时甲状腺激素稳态和能量代谢的变化。本临床方案旨在利用临床中心代谢单元新开放的呼吸室，在体内研究暴露于环境温度轻度变化期间循环甲状腺激素的变化。该方案最近已获得IRB批准，目前正在招募健康志愿者。目前，已有14名志愿者完成了这项研究，我们预计将在本历年年底前完成数据收集。 07-DK-0219营养基因组学干预研究膳食谷甾醇对脂质、葡萄糖和能量代谢的作用。这是对ABCG 8突变携带者和性别匹配的未受影响的兄弟姐妹的营养基因组学干预，旨在研究ABCG 8基因突变和植物甾醇膳食含量之间的相互作用的影响。我们假设ABCG 8基因突变的携带者在接受高谷甾醇饮食的挑战时将进一步改善代谢综合征指数，并且在接受低谷甾醇饮食的治疗时将向非携带者对照回归。本研究在宾夕法尼亚州兰开斯特公司的旧秩序阿米什人人群中进行，这是一个ABCG 8突变患病率高的创始人人群。目前，两对同胞已经完成了第一阶段的研究。 08-DK-0165内源性分泌胆汁酸（BA）刺激期间甲状腺激素稳态和能量代谢变化。体外和动物数据表明，胆汁酸以内分泌方式激活T4转化为T3，最终导致能量消耗增加。该翻译方案旨在研究健康志愿者中大量营养素和胆汁酸在食物热效应中的作用。该方案已获得NIDDK/NIAMS IRB的批准，目前正在招募健康志愿者。

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 ten patients have completed both phases of the study. The preliminary results of this study have been presented at the Annual Endocrine Society meeting. 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 09. 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 protocol has recently been approved by the IRB and the recruitment of healthy volunteers is currently ongoing. Presently 14 volunteers have completed the study, and we expect to complete the collection of the data by the end of the calendar year. 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 two sib-pairs have completed the first phase 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 the recruitment of healthy volunteers is currently ongoing.