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

良性、非癌症的肾上腺结节很常见，经常会产生过多的类固醇应激激素皮质醇(一种被称为轻度自主皮质醇分泌的情况)。据估计，在70岁以上的人口中，有3%的人患有Mac，这与虚弱、糖尿病、心脏病发作和中风的风险增加有关。皮质醇对许多组织都有深远的影响，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来限制Mac患者皮质醇过量的影响。在组织(脂肪、肌肉、肝脏、骨骼、大脑)中，我们已经证明，通过一种名为11B-羟基类固醇脱氢酶1(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，并导致了我们在Mac患者中观察到的许多不良症状。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影响。我们现在想看看在Mac患者身上使用类似的方法是否通过减少体内自然产生的皮质醇的作用来改善他们的症状，皮质醇在他们体内的水平略高。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、大脑功能和骨骼健康，这些都是有充分证据证明会对Mac患者产生不利影响的。我们的目标是发现11B-HSD1抑制剂(Xanamem)是否能改善这些情况。此外，我们将对11B-HSD1抑制剂的给药时间与皮质醇水平的最高值相一致，以评估其有益效果。这些研究不仅将证明11B-HSD1在MACs发展中的基础作用，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未来药物治疗的可能性。

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.