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  • Title: The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome.
    Author: Stimson RH, Walker BR.
    Journal: Horm Mol Biol Clin Investig; 2013 Sep; 15(2):37-48. PubMed ID: 25436731.
    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.
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