MICA: Dissecting the Contribution of glucocorticoid metabolism in Mild Autonomous Cortisol Secretion (DC-MACS)

MICA：剖析糖皮质激素代谢对轻度自主皮质醇分泌 (DC-MACS) 的贡献

基本信息

批准号：
MR/W015455/1
负责人：
Jeremy Tomlinson
金额：
$ 156.94万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW015455%2F1
关键词：
MICA Dissecting Contribution glucocorticoid metabolism

项目摘要

Benign, non-cancerous, nodules of the adrenal gland are common and can frequently produce too much of the steroid stress hormone, cortisol (a condition called mild autonomous cortisol secretion, MACS). It is estimated that 3% of the population aged over 70 have MACS and this is associated with increased risks of frailty, development of diabetes, heart attacks and strokes. Cortisol has profound effects on many tissues including the circulatory system, fat, muscle and the brain. Currently there is no specific treatment to limit the effects of the excess cortisol in patients with MACS. In tissues (fat, muscle, liver, bone, brain) we have shown that there is further generation of excess cortisol through the activity of an enzyme called 11B-hydroxysteroid dehydrogenase type 1 (11B-HSD1); this exacerbates the problem of too much cortisol and drives many of the adverse features that we observe in patients with MACS. Using a drug to block the action of this enzyme, a so-called 11B-HSD1 inhibitor, we have been able to block the undesirable effects of prescribed steroids that have been taken by mouth. We now want to see if using a similar approach in patients with MACS improves their symptoms by reducing the action of the naturally occurring cortisol that is present at slightly higher levels in their bodies. We will use very sensitive techniques to look at how the body handles glucose, as well as fat and muscle distribution, brain function and bone health, which are all well-documented to be adversely affected in patients with MACS. We aim to discover if these are improved with an 11B-HSD1 inhibitor (Xanamem). In addition, we will time the administration of the 11B-HSD1 inhibitor to coincide with the highest cortisol levels to assess the beneficial effect. These studies will not only demonstrate the fundamental role of 11B-HSD1 in the development of MACS, but also begin to explore the potential that 11B-HSD1 inhibitors may be an option for future drug treatment in these patients where currently none are available.

良性、非癌性的肾上腺结节很常见，并且经常会产生过多的类固醇应激激素皮质醇（一种称为轻度自主皮质醇分泌，MACS 的病症）。据估计，70 岁以上人口中有 3% 患有 MACS，这与虚弱、患糖尿病、心脏病和中风的风险增加有关。皮质醇对许多组织具有深远的影响，包括循环系统、脂肪、肌肉和大脑。目前还没有特定的治疗方法可以限制过量皮质醇对 MACS 患者的影响。我们已经证明，在组织（脂肪、肌肉、肝脏、骨骼、大脑）中，通过 11B-羟基类固醇脱氢酶 1 型 (11B-HSD1) 的酶的活性，会进一步产生过量的皮质醇；这加剧了皮质醇过多的问题，并导致我们在 MACS 患者中观察到的许多不良特征。通过使用一种药物来阻断这种酶的作用，即所谓的 11B-HSD1 抑制剂，我们已经能够阻止口服处方类固醇的不良反应。我们现在想看看对 MACS 患者使用类似的方法是否可以通过减少体内水平稍高的天然皮质醇的作用来改善他们的症状。我们将使用非常敏感的技术来观察身体如何处理葡萄糖，以及脂肪和肌肉的分布、大脑功能和骨骼健康，这些都有充分的证据表明 MACS 患者会受到不利影响。我们的目标是发现 11B-HSD1 抑制剂 (Xanamem) 是否可以改善这些症状。此外，我们将 11B-HSD1 抑制剂的给药时间与最高皮质醇水平一致，以评估有益效果。这些研究不仅将证明 11B-HSD1 在 MACS 发展中的基本作用，而且还将开始探索 11B-HSD1 抑制剂可能成为这些目前尚无药物治疗的患者的未来药物治疗选择的潜力。