Abstract
Glucocorticoid action is mediated by glucocorticoid receptor (GR), which upon cortisol binding is activated and regulates the transcriptional expression of target genes and downstream physiological functions. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol. Since cortisol is also produced through biosynthesis in the adrenal glands, the total cortisol level in a given tissue is determined by both the circulating cortisol concentration and the local 11β-HSD1 activity. 11β-HSD1 is expressed in liver, adipose, brain, and placenta. Since it contributes to the local cortisol levels in these tissues, 11β-HSD1 plays a critical role in glucocorticoid action. The metabolic symptoms caused by glucocorticoid excess in Cushing’s syndrome overlap with the characteristics of the metabolic syndrome, suggesting that increased glucocorticoid activity may play a role in the etiology of the metabolic syndrome. Consistent with this notion, elevated adipose expression of 11β-HSD1 induced metabolic syndrome-like phenotypes in mice. Thus, 11β-HSD1 is a proposed therapeutic target to normalize glucocorticoid excess in a tissue-specific manner and mitigate obesity and insulin resistance. Selective inhibitors of 11β-HSD1 are under development for the treatment of type 2 diabetes and other components of the metabolic syndrome.
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Wang, M. (2011). Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 in Antidiabetic Therapy. In: Schwanstecher, M. (eds) Diabetes - Perspectives in Drug Therapy. Handbook of Experimental Pharmacology, vol 203. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-17214-4_6
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