title: Inhibitors of 11β-hydroxysteroid dehydrogenase type 1 in antidiabetic therapy.
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.
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Mail Stop 29-1-A, Thousand Oaks, CA 91320, USA. mwang@amgen.com
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005938:Glucocorticoids / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance; D024821:Metabolic Syndrome / Q000503:physiopathology; D051379:Mice
chemical_list: D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007004:Hypoglycemic Agents; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1