title: 11beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle.
abstract: OBJECTIVE
  Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11beta-HSD1 inhibitors improve insulin sensitivity.
  
  
  METHODS
  Rodent and human cell cultures, whole-tissue explants, and animal models were used to determine the impact of glucocorticoids and selective 11beta-HSD1 inhibition upon insulin signaling and action.
  
  
  RESULTS
  Dexamethasone decreased insulin-stimulated glucose uptake, decreased IRS1 mRNA and protein expression, and increased inactivating pSer(307) insulin receptor substrate (IRS)-1. 11beta-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active glucocorticoid. A1 (selective 11beta-HSD1 inhibitor) abolished enzyme activity and blocked the increase in pSer(307) IRS1 and reduction in total IRS1 protein after treatment with 11DHC but not corticosterone. In C57Bl6/J mice, the selective 11beta-HSD1 inhibitor, A2, decreased fasting blood glucose levels and improved insulin sensitivity. In KK mice treated with A2, skeletal muscle pSer(307) IRS1 decreased and pThr(308) Akt/PKB increased. In addition, A2 decreased both lipogenic and lipolytic gene expression.
  
  
  CONCLUSIONS
  Prereceptor facilitation of glucocorticoid action via 11beta-HSD1 increases pSer(307) IRS1 and may be crucial in mediating insulin resistance in skeletal muscle. Selective 11beta-HSD1 inhibition decreases pSer(307) IRS1, increases pThr(308) Akt/PKB, and decreases lipogenic and lipolytic gene expression that may represent an important mechanism underpinning their insulin-sensitizing action.
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, U.K.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Morgan
authors.forename: Mark
authors.initials: M
authors.lastname: Sherlock
authors.forename: Laura L
authors.initials: LL
authors.lastname: Gathercole
authors.forename: Gareth G
authors.initials: GG
authors.lastname: Lavery
authors.forename: Carol
authors.initials: C
authors.lastname: Lenaghan
authors.forename: Iwona J
authors.initials: IJ
authors.lastname: Bujalska
authors.forename: David
authors.initials: D
authors.lastname: Laber
authors.forename: Alice
authors.initials: A
authors.lastname: Yu
authors.forename: Gemma
authors.initials: G
authors.lastname: Convey
authors.forename: Rachel
authors.initials: R
authors.lastname: Mayers
authors.forename: Krisztina
authors.initials: K
authors.lastname: Hegyi
authors.forename: Jaswinder K
authors.initials: JK
authors.lastname: Sethi
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
authors.forename: David M
authors.initials: DM
authors.lastname: Smith
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D005938:Glucocorticoids; D007328:Insulin; D012333:RNA, Messenger; D012313:RNA; D003907:Dexamethasone; D003847:Deoxyglucose; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
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