title: Cortisone induces insulin resistance in C2C12 myotubes through activation of 11beta-hydroxysteroid dehydrogenase 1 and autocrinal regulation.
abstract: The enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) is known to catalyse inactive glucocorticoids into active forms, and its dysregulation in adipose and muscle tissues has been implicated in the development of metabolic syndrome. To delineate the molecular mechanism by which active cortisol has an antagonizing effect against insulin, we optimized the metabolic production of cortisol and its biological functions in myotubes (C2C12). Myotubes supplemented with cortisone actively catalysed its conversion into cortisol, which in turn abolished phosphorylation of Akt in response to insulin treatment. This led to diminished uptake of insulin-induced glucose. This was corroborated by the application of 11β-HSD1 inhibitor glycyrrhetinic acid and a glucocorticoid receptor antagonist RU-486, which reversed completely the antagonizing effects of cortisol on insulin action. Therefore, development of specific inhibitors targeting 11β-HSD1 might be a promising way to improve impaired insulin-stimulated glucose uptake.
authors.affiliation: College of Pharmacy, Keimyung University, Daegu, South Korea.
authors.forename: Seung Yeon
authors.initials: SY
authors.lastname: Park
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Bae
authors.forename: Young Sik
authors.initials: YS
authors.lastname: Cho
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019898:Autocrine Communication; D002460:Cell Line; D003348:Cortisone / Q000378:metabolism* / Q000494:pharmacology; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D015735:Mifepristone / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D007328:Insulin; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D005947:Glucose; D006034:Glycyrrhetinic Acid; D003348:Cortisone; D006854:Hydrocortisone
keywords: 11β-hydroxysteroid dehydrogenase 1; cortisol; glucose uptake; insulin resistance; myotubes