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

• 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

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.

肾上腺良性、非癌性结节很常见，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的疾病，MACS）。据估计，70岁以上的人口中有3%患有MACS，这与虚弱，糖尿病，心脏病发作和中风的风险增加有关。皮质醇对许多组织有深远的影响，包括循环系统、脂肪、肌肉和大脑。目前，没有特定的治疗方法来限制MACS患者过量皮质醇的影响。在组织（脂肪，肌肉，肝脏，骨骼，大脑）中，我们已经证明，通过一种称为11B-羟基类固醇脱氢酶1型（11B-HSD 1）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，并导致了我们在MACS患者中观察到的许多不良特征。使用一种药物来阻断这种酶的作用，一种所谓的11B-HSD 1抑制剂，我们已经能够阻断口服处方类固醇的不良作用。我们现在想看看在MACS患者中使用类似的方法是否可以通过减少他们体内天然存在的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，以及脂肪和肌肉分布，脑功能和骨骼健康，这些都是有据可查的，对MACS患者有不利影响。我们的目标是发现这些是否与11B-HSD 1抑制剂（Xanamem）改善。此外，我们将对11B-HSD 1抑制剂的给药时间进行计时，以与最高皮质醇水平相一致，以评估有益效果。这些研究不仅将证明11 B-HSD 1在MACS发展中的基本作用，而且还将开始探索11 B-HSD 1抑制剂可能成为这些患者未来药物治疗的一种选择的潜力，而目前还没有可用的药物。

项目成果

Treating the Side Effects of Exogenous Glucocorticoids; Can We Separate the Good From the Bad?

• DOI: 10.1210/endrev/bnad016
• 发表时间: 2023-11-09
• 期刊: Endocrine reviews
• 影响因子: 20.3