title: The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome.
abstract: 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.
authors.affiliation: Centre for Cardiovascular Science, Queen’s Medical Research Institute, Edinburgh, EH16 4TJ, UK. roland.stimson@ed.ac.uk
authors.forename: Roland H
authors.initials: RH
authors.lastname: Stimson
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone