Stimson Roland H, Walker Brian R
Centre for Cardiovascular Science, Queen’s Medical Research Institute, Edinburgh, EH16 4TJ, UK.
Horm Mol Biol Clin Investig. 2013 Sep;15(2):37-48. doi: 10.1515/hmbci-2013-0015.
The cortisol regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels, particularly in the liver and adipose tissue. The importance of this enzyme in causing metabolic disease was highlighted by transgenic mice which over- or under-expressed 11β-HSD1; consequently, selective 11β-HSD1 inhibitors have been widely developed as novel agents to treat obesity and type 2 diabetes mellitus (T2DM). This review focuses on the importance of 11β-HSD1 in humans which has been more difficult to ascertain. The recent development of a deuterated cortisol tracer has allowed us to quantify in vivo cortisol production by 11β-HSD1. These results have been surprising, as cortisol production rates by 11β-HSD1 are at least equivalent to that of the adrenal glands. The vast majority of this production is by the liver (>90%) with a smaller contribution from subcutaneous adipose tissue and possibly skeletal muscle, but with no detectable production from visceral adipose tissue. This tracer has also allowed us to quantify the tissue-specific regulation of 11β-HSD1 observed in obesity and obesity-associated T2DM, determine the likely basis for this dysregulation, and identify obese patients with T2DM as the group most likely to benefit from selective inhibition of 11β-HSD1. Some of these inhibitors have now reached Phase II clinical development, demonstrating efficacy in the treatment of T2DM. We review these results and discuss whether selective 11β-HSD1 inhibitors are likely to be an important new therapy for metabolic disease.
皮质醇再生酶11β-羟基类固醇脱氢酶1型（11β-HSD1）可放大组织糖皮质激素水平，尤其是在肝脏和脂肪组织中。转基因小鼠过度表达或低表达11β-HSD1，凸显了这种酶在引发代谢性疾病中的重要性；因此，选择性11β-HSD1抑制剂已被广泛开发为治疗肥胖症和2型糖尿病（T2DM）的新型药物。本综述聚焦于11β-HSD1在人类中的重要性，而这一点更难确定。最近开发的氘代皮质醇示踪剂使我们能够在体内量化11β-HSD1产生的皮质醇。这些结果令人惊讶，因为11β-HSD1产生的皮质醇速率至少与肾上腺相当。这种产生的绝大部分来自肝脏（>90%），皮下脂肪组织和可能的骨骼肌贡献较小，而内脏脂肪组织未检测到产生。这种示踪剂还使我们能够量化在肥胖症和肥胖相关T2DM中观察到的11β-HSD1的组织特异性调节，确定这种调节异常的可能基础，并确定患有T2DM的肥胖患者是最可能从选择性抑制11β-HSD1中获益的群体。其中一些抑制剂现已进入II期临床开发，显示出对T2DM的治疗效果。我们回顾这些结果，并讨论选择性11β-HSD1抑制剂是否可能成为代谢性疾病的一种重要新疗法。
